Mental Disorders and Genetics: Bridging

the Gap Between Research and Society

September 1994

NTIS order #PB95-109690

GPO stock #052-003-01392-4

Foreword

T

ethnological advances in genetics drive the search for mental disorder

genes. Although the research results have been complicated and, at

times, confusing, some important discoveries have emerged. Researchers have located and identified genes associated with A1zheimer’s disease. A sound and extensive bank of data provides evidence for the

role of genetic factors in schizophrenia and major mood disorders. Other, albeit fewer data lend support to the hypothesis that genetic factors contribute to

panic and obsessive-compulsive disorders.

What we know about the genetics of mental disorders, and what we may

learn, has implications for research, clinical practice, and society-at-large. A

workshop cosponsored by the Office of Technology Assessment and the National Institute of Mental Health focused on these implications. It was

prompted by the 1992 report The Biology of Mental Disorders, which was requested by House Committees on Appropriations; Energy and Commerce;

Science, Space, and Technology; Veterans Affairs; and the Senate Subcommittee on Science, Technology, and Space of the Committee on Commerce, Science, and Transportation. Senator Edward M. Kennedy, Chairman of the

Senate Committee on Labor and Human Resources, also endorsed the 1992 report request. This background paper relays the workshop participants’ discussion, augmenting it with other information sources. OTA gratefully

acknowledges the assistance of workshop participants as well as other experts

who assisted with this work. But as with all OTA products, responsibility for

the content is OTA’S alone.

A key focus of the workshop was the impact of genetic research on people

with mental disorders and their family members. Workshop testimony made

clear that they want to know the latest research discoveries. They are encouraged by research progress and the possibility of improved treatment. They

worry about the genetic risk for a serious mental disorder that their family

members face. They want to be more equal partners in research. They welcome

the de-stigmatizing influence of biomedical research. Yet they fear its potential abuse. However, as the background paper title suggests, a gap separates research-derived information on genetics and mental illness from the people

who desire it. This background paper offers one resource in closing this gap.

ROGER C. HERDMAN

Director

● Ill
Preject Staff

Clyde J. Behney

Assistant Director, OTA

Sean R. Tunis

Health Program Director

ADMINISTRATIVE STAFF

Beckie Erickson

Office Administrator

Carolyn Martin

Word Processing Specialist

Daniel B. Carson

PC Specialist

Carolyn Swarm

PC Specialist

LAURA LEE HALL

Project Director

Jacqueline T. Keller

Research Analyst

Arna M. Lane

Editor

PUBLISHING STAFF

Mary Lou Higgs

Manager, Publishing Services

Denise Felix

Production Editor

Dorinda Edmondson

Electronic Publishing Specialist

Susan Hoffmeyer

Graphic Designer

Iv
1

2

3

Introduction 1

Emergent Workshop Themes 6

Chapter 1 References 7

Research Results 9

Genetic Research Primer 10

Alzheimer’s Disease 12

Schizophrenia 14

Major Mood Disorders 17

Panic Disorder 19

Obsessive-Compulsive Disorder 20

Summary and Conclusions 21

Chapter preferences 24

implications for Society 29

Ethics and Research 30

Genetic Counseling 36

Public Perceptions and Social Implications 44

Summary and Conclusions 49

Chapter preferences 50

APPENDIXES

A Workshop Participants 55

B Acknowledgments 57

contents

V
Introduction

I

n January 1993, the Office of Technology Assessment

(OTA) and the National Institute of Mental Health (NIMH)

convened a workshop-Understanding the Role of Genetic

Factors in Mental Illness: Bridging the Gap Between Research and Society (box 1-1 ). It reportedly is the first comprehensive discussion focused specifically on the implications of

genetics and mental disorders research (5).

All participants acknowledged that the subject of genetics and

mental disorders is a complex, consequential, and controversial

one. Researchers have long examined the role of inheritance in

mental disorders, accumulating evidence over the course of this

century. Fast-paced advances in genetics in the 1980s catalyzed

more intense interest in the inheritance of mental disorders, and

researchers brought to bear new and powerful research tools on

these seemingly unfathomable diseases.

The result was exhilarating optimism followed by intense

skepticism. The locations of genes linked to bipolar disorder,

Alzheimer’s disease, and schizophrenia were announced to much

fanfare. Media attention and optimism soon plummeted, however, when emerging data proved perplexing, some findings were

retracted, and further progress evaded researchers. Naysayers

condemned outright the idea that genes contribute to mental disorders at all.

That the genetics of mental disorders would prove difficult to

resolve comes as no surprise to long-time experts in the field.

“The primarily negative results. . . have led some to become pessimistic. However, I cannot share this pessimism. As a scientist

committed to solving this problem, I have always believed that

finding genes for schizophrenia would not be easy” (10). What

does give cause for alarm is the either-or reduction of this issue: 11
2 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Understanding the Roie of Genetic Factors in Mental Illness: Bridging the Gap Between Research

and Society

AGENDA

Thursday after eon. January n r 2 1, 1993

1:00-1:30 Opening Remarks

Herbert Paroles, M. D., Workshop Chair

Frederick K. Goodwin, M. D., Director, NIMH

Roger Herdman, M. D., Assistant Director, OTAl

Laura Lee Hall, Ph. D., Senior Analyst, OTA

Kate Berg, Ph. D., Schizophrenia Research Branch, NIMH

1:30-1:45 introduction of Workshop Panelists

1:45-3:15 Current Scientific Understanding of Genetic Factors in Mental Disorders

That genetic factors contribute to major mental disorders has been established by various types of studies, However, the extent and nature of the genetic input have not been established and are the subject of

intensive research. During the discussion, panelists will consider the following questions:

What is the evidence that severe mental disorders—schizophrenia, major mood and anxiety disorders,

and Alzheimer’s disease-have a genetic component?

What models exist to explain the genetic contribution? What are the limits of these models?

What is the status of linkage analysis studies of mental disorders?

3:30-5:00 Scientific Findings and Recurrence Risks

Even without complete understanding of the precise role that genetic factors play in major mental disorders, individuals with these conditions and their family members have begun requesting information on

recurrence risk. In their discussion, panelists will consider the following questions:

Based on current data, what information about recurrence risks can be given?

What are the limitations of recurrence risk information?

Will genetic tests for major mental disorders be available in the near future?

What concerns surround the relay of information concerning genetic risk for a mental disorder?

5:00-5:15 Comments by Workshop Observers

5:15-5:30 Summary by Dr. Paroles

Fridav, January 22, 1993

9:15-9:30 Opening Remarks by Dr. Paroles

9:30-10:45 The Genetic Counseling Milieu

Inevitably, the relay of information on health and genetic status in the clinical setting is laden with challenges. These challenges are amplified in the case of the genetics of mental disorders, in which the con1 Dr Herdman was appointed director of OTA in May 1993
Chapter 1 Introduction 13

tribution of both genetic and nongenetic factors is not yet completely understood. The panelists will address the issues that surround the relay of this information in the clinical setting, including the following

questions:

What is the utility of genetic counseling for mental disorders given the current state of knowledge?

What benefits and limits do various professions—psychiatry, genetic counseling, social work—bring to

genetic counseling for mental disorders?

What additional training may be needed to help care-providers remain current in their understanding of the

genetic factors involved in mental disorders?

What family planning considerations emerge—e.g., varying perceptions of burden of illness, pregnancy

and child-bearing issues?

11:00-12:15 Perceptions of Genetics and Mental Illness

Ignorance of and negative attitudes attached to mental illness abound in our society. Actual information

about the genetic components of mental disorders counters many of the erroneous and cruel perceptions

about the causes of these conditions. However, the complexity of the genetics of mental illness, and the

interplay of nongenetic factors, impedes the easy relay of accurate information. In their discussion, panelists will consider the following questions:

Given the potency of reports about gene discoveries, how best can research results be disseminated to

the scientific and lay press?

What lessons can be drawn from experience with the stigmatization of other genetic illnesses?

Are there needs for pro-active efforts to accurately educate the public on these issues?

1:30-3:15 Ethical and Legal Issues

Ethical and legal issues often arise with scientific advances. Genetic research in mental illness is no exception. Questions arise in relation to the actual collection of data, the way in which data are perceived, the

context of clinical practice, and the broader social sphere. In discussing relevant ethical and legal concerns, the panelists may consider the following questions:

What ethical and legal issues surround pedigree studies? What safeguards can be incorporated to protect

subject rights without obstructing needed research?

Are there special informed consent issued involving patients+ children, patients with dementia, actively

psychotic patients?

What issues are raised by subject recruitment?

Who should have access to information on patients’ and family members’ current or future health and genetic status that is unveiled in research? Researchers? Institutions funding and supporting research? Other family members? Subjects themselves? Personal clinicians? Insurance companies or employers?

3:30-5:15 An Agenda for Future Research

Given the current state of knowledge and the discussion at the workshop, what kinds of basic, clinical,

and social science research are possible? Needed?

5:15-5:30 Comments by Workshop Observers

5:30-5:45 Concluding Comments by Dr. Paroles
4 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

scHIzoPhrenia

and

GENETIC RISKS

I

National Alliance for the Mentally Ill

The National Alliance for the Mentally Ill (NAMI) published the

second printing of this 1 l-page pamphlet on schizophrenia

and genetic risks in 1992. The NAMI pamphlet represents one

of the few, if not the only, source of information for people with

mental disorders, their family members, and mental health

care providers. The text of this unique resource describes

genetic counseling, schizophrenia, and what is known about

the inheritance of this condition.

“the mental disorder gene has been found” versus

“no genetic contribution exists at all.” Vacillating

between jubilant claims of successful gene finds

and reactionary doubts impedes the sophisticated

and tenacious pursuit needed for a better understanding of the genetic and nongenetic factors involved in mental disorders. As noted by leading

geneticists, “the main thrust of modem molecular

medicine is towards precisely defining etiology

both at the molecular level and at the level of interplay between genes and environment” (6).

The prevailing controversy also obscures the

implications of this research for people with mental disorders and their families. Representatives

from NIMH and consumer organizations testify to

the increasing number of consumer requests for

information about the genetics of mental disorders

(1,4). Little communication of data from researchers to clinical care-providers and consumers

occurs. The ethical and social implications emerging from the conduct of research and research

results have received even less notice, in contradistinction to genetic research in general (box

1-2).

The workshop follows up on a 1992 OTA report-The Biology of Mental Disorders—requested by several House Committees and

endorsed by Senator Edward M. Kennedy, Chairman of the Senate Committee on Labor and Human Resources (11). The report reviewed data

concerning the contribution of genetic factors to

several severe mental disorders, described methodologies used in the studies, and broached several policy issues relevant to this area of research.

NIMH, with its ongoing and substantial support

for research into the genetics of mental disorders

(table l-l), as well as its interests in related areas

of public policy, supported further exploration of

the issues raised by genetic research. Building on

this base, the OTA-NIMH workshop attended to

four major topics:

the current understanding of genetic factors in

mental disorders, including Alzheimer’s disease, schizophrenia, major mood disorders,

panic disorder, and obsessive-compulsive disorder;

ethical issues in research;

the communication of genetic information in

the clinical setting; and

perceptions and social implications of genetics

and mental disorders.

1 Requesters included the House Committees on Appropriations; Energy and Commerce; Science, Space, and Technology; Veteran Affairs;

and the Senate Subcommittee on Science, Technology, and Space of the Committee on Commerce, Science, and Transportation,
Chapter 1 Introduction 15

Since ifiscal year 1988, Congress and the executive branch have made a commitment to determine the

location of all human genes (e.g., as has been done for sickle cell anemia, cystic fibrosis, and Tay-Sachs

disease). The Human Genome Project is estimated to be a 15-year, $3-billion project. It has been undertaken with the expectation that enhanced knowledge about genetic disorders, increased understanding of

gene-environment interactions, and improved genetic diagnoses can advance therapies for the 4,000 or so

currently recognized human genetic conditions.

To address the ethical, legal, and social issues of the Human Genome Project, and to define options to

address them, the National Institutes of Health (NIH) and the Department of Energy (DOE) each funds an

Ethical, Legal, and Social Issues (ELSI) Program. Funds for each agency’s ELSI effort derive from a setaside of 3 to 5 percent of appropriations for the year’s genome initiative budget. In fiscal year 1991, DOE’s

ELSI spending was $1.44 million (3 percent); in fiscal year 1992, $1.77 million (3 percent). Its fiscal year

1993 spending was targeted at $1.87 million. NIH’s ELSI spending for fiscal years 1990 and 1991 has been

$1.56 million (2.6 percent) and $4.04 million (4.9 percent) respectively. NIH’s ELSl spent $5.11 million (5

percent) for fiscal year 1992 and aimed to spend $5.30 million in fiscal year 1993 (5 percent).

ELSI funds bioethics research related to the Human Genome Project to expand the knowledge base in

this area. The program operates in the model of peer review competition for grant funds, The ELSI Working

Group, which advises both programs, initially framed the agenda and established priority research areas.

Nevertheless, the nature of grant programs means the ultimate direction evolves from the bottom up—i.e.,

from the individual perspectives of researchers pursuing independent investigations—rather than from the

top down—i.e., through policy makers or an overarching federal body. Furthermore, no formal mechanism

exists for ELS1-funded research findings to directly make their way back into the policy process, And although the ELSI programs have a large funding base for grants, they lack resources for in-house policy

analysis. The ELSI Working Group, however, has played a role in policy analyses related to genetics and

the Americans With Disabilities Act, cystic fibrosis carrier screening, and genetic research involving several family members.

SOURCE U S. Congress, Off Ice of Technology Assessment, Biomedical Ethics U.S. Public Policy—BackgmundPaper, OTA-BPBBS-105 (Washington, DC U S Government Printing Office, June 1993).

The text of this background paper recounts the Workshop panelists agreed that what we curworkshop discussion, supplementing it with information from the previous OTA report and new

research data and sources.

We can conclude that genetic factors contribute

to many of the major mental disorders discussed

in this report. Indeed, researchers have located and

in some cases identified specific genes involved in

Alzheimer’s disease. The consistent evidence for

a genetic contribution to schizophrenia and major

mood disorders, together with the rapid advances

in molecular genetics, makes continued research

in this area a promising endeavor. But progress is

likely to be slow, given the complexity of these

conditions.

rently know about the genetics of mental disorders

has implications for our society. Genetic research

into mental disorders raises ethical issues for

people with these conditions and their family

members who participate in such studies; these issues warrant ongoing consideration. Individuals

with mental disorders and their family members

seek information about the risk of mental disorders that their other family members or offspring

may face. Available data can shed light on this

risk. But such information is generally not specific or detailed. Furthermore, most mental health

care-providers and genetic counselors are not

equipped to offer genetic counseling services for
6 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Total costs of Number of Percentage of

genetic research grants total budget

Division of clinical $25,629,833b

88 15Y0

Research

Division of Basic Brain 13,351,201 55 10.9

and Behavioral Sciences

NIMH total 38,981,034 143 8.7

a

These figures represent funding for research where the primary focus is human genetics of mental disorders.

bof thisflgure,$2,0g0,812, or 8.14 percent, of the Division of Clinical Research’s genetic budget is devoted to Diagnostic Centers Cooperative Agreements,

SOURCE: National Institute of Mental Health, 1992.

mental disorders. Finally, many individuals with

mental disorders and their family members find

comfort in the ongoing pursuit of genes involved

in mental disorders. These genetic advances as

well as society’s perception of them could present

problems, however, if used in a discriminatory

fashion.

EMERGENT WORKSHOP THEMES

While the workshop discussion considered a variety of topics, a few themes emerged that imbued

nearly each subject brought up by the workshop

participants:

the transitional stage of research;

the specious but persistent nature-versus-nurture debate;

family as a key focus of concern;

negative attitudes attached to mental disorders;

and

the information gap.

The transitional stage of research. Several

workshop participants acknowledged that research of the genetics of mental disorders has entered a transitional stage, characterized by rapid

technological developments, complex research issues, and unpredictable course. Difficulties presented by the research stubbornly persist. Although

several experts have adeptly described the problems that originally beset linkage analysis of mental disorders, no one can fully explain the

nonreplication and reversal of results characteristic of the field to date (3,8,9). Also, scientists

grapple with fundamental issues-diagnostic

categories, subtypes of disorders, and the bestfitting genetic models—as they fashion more

sophisticated hypotheses. These questions juxtapose continued efforts and advances. Research

tools are evolving rapidly. Scientists can more

promptly confirm or disclaim data implicating a

link between a genetic location and mental disorder. Researchers resolutely trudge forward with

linkage studies, collecting data and specimens

from large, extended families and other pedigree

types.

This transitional stage does not negate the accrued evidence from family, twin, and adoption

studies strongly supporting a genetic contribution

to some mental disorders. Rather, this stage implicates the complexity of these conditions and their

underlying causes. It also complicates decisions

about research support, educational efforts, and

speculation about social implications.

The specious nature-versus-nurture debate.

As already noted, this debate persists. Scientists,

commentators, and analysts often frame data from

research in all-or-nothing terms: a single gene

completely explains a disorder or genes have no

impact whatsoever on these conditions. Rebutting

such simplistic conclusions, data point to heterogeneous causes, including genetic and nongenetic

factors, at play in mental disorders. Nonetheless,

nature-versus-nurture sloganeering too frequently

holds sway in media presentations and analyses.
This false polarization fuels continued controversy, fear, and ignorance, thus compelling the dissemination of factually correct information.

Family as a key focus of concern. When talking about genetics, one is necessarily talking

about families. Research studies involve not just a

single participant; whole families may participate. Family members and prospective spouses

may seek information about the risk of mental disorder in offspring. Public policies about insurance

coverage and employment impact on people with

mental disorders and family members alike. Unfortunately, policies that guide the way in which

research is performed, clinical information is

relayed, and legislation is fashioned have yet to

grapple fully with family involvement.

Negative attitudes attached to mental disorders. No discussion of mental disorders can ignore the stigma and discrimination attached to

these conditions. Although attitudes are apparently improving (2), often people with mental disorders are feared, avoided, and disparaged (for

review of data, see 11,12). Their family members

have long stood accused of poor parenting or neglect. This reality of mental disorders colored every issue discussed at the workshop, including

family support for research, concerns about privacy of research and clinical information, and skepticism among consumers and other analysts about

the application of genetic technology.

The information gap. Complex data, controversy, and negative attitudes result all too often in

ignorance and misinformation about mental disorders and genetics. Workshop panelists pointed

out the many faces of this information gap. People

with mental disorders and their family members

hunger for information on genetic research to help

them make sense of their condition and the confusing reports that appear in the media. In order to

provide this information to consumers, mental

health care-providers need a better understanding

of genetic data as well as the principles of genetic

counseling; genetic counselors require information on mental disorders. Researchers and panels

reviewing research ethics require information on

the risks and unique issues presented by genetics

and mental disorders. Members of the press also

Chapter 1 Introduction

need accurate and understandable information

17

to

assist them in gaining perspective on newly reported findings (7). Finally, accurate information

directed at society at large—about genetics and

mental disorders—may help prevent or at least diminish injurious social perceptions and policies.

CHAPTER 1 REFERENCES

1.

2.

3.

4.

5.

6.

7.

Berg, K., remarks at “Understanding the Role

of Genetic Factors in Mental Illness: Bridging

the Gap Between Research and Society,” a

workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

Burgmann, F. D., Executive Vice President,

National Depressive and Manic Depressive

Association, Chicago, IL, personal communication, July 30, 1994.

Cox, D. R., remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

Flynn, L., remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

Leshner, A., remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

McGuffin, P., Owen, M. J., O’Donovan,

M. C., et al., Seminars in Psychiatric Genetics

(London, UK: Gaskell, 1994).

Nelkin, D., remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and So-
8 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

8.

9.

ciety,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

Risch, N., “Genetic Linkage and Complex

Diseases, With Special Reference to Psychiatric Disorders,” Genetic Epidemiology 7:3- 16,

1990.

Risch, N., remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

10.

11.

12<

Tsuang, M.T., Professor of Psychiatry and Director of Psychiatric Epidemiology and Genetics, Harvard University, Cambridge, MA,

personal communication, May 9, 1994.

U.S. Congress, Office of Technology Assessment, The Biology ofMental Disorders, OTABA-538 (Washington, DC: U.S. Government

Printing Office, September 1992).

U.S. Congress, Office of Technology Assessment, Psychiatric Disabilities, Employment,

and the Americans With Disabilities Act,

OTA-BP-BBS-124 (Washington, DC: U.S.

Government Printing Office, March 1994).
Research

Results 2

D

somes

iscovery of the chromosome location of the Huntington’s

disease gene more than 10 years ago marked a turning

point in genetic research (25). Advances in molecular genetics permitted the extensive search of human chromofor specific disease genes. This approach has since

dominated the study of genetic diseases, with some stunning results. Locating more than one human gene each day, in the past

year alone, researchers have zeroed in on genes linked to Lou

Gehrig’s disease (amyotrophic lateral sclerosis or ALS), a common form of colon cancer, and others. Upon learning the genetic

address of disease genes, not only have diagnostic tests been developed for several conditions (e.g., cystic fibrosis and Huntington’s disease), but the very nature of some of the gene defects has

been exposed and medical treatment based on gene replacement

is under intensive investigation.

Without a doubt, molecular genetics is transforming medicine.

The revolution in genetics also has influenced mental disorders

research. The search for genes linked to schizophrenia, bipolar

disorder (manic-depression), and other mental disorders seemingly found early success, the results of which were highly publicized. But with the exception of Alzheimer’s disease, the location

of a mental disorder gene has yet to be confirmed.

How should we interpret the current status of mental disorders

genetics? Do mental disorders have a genetic component? If so,

how big a role do genes play in these conditions and how are they

transmitted? Any discussion of the clinical and social implications of mental disorders genetics necessarily begins with an accurate understanding of the scientific data. Discussion at the first

day of the workshop sponsored by the Office of Technology

Assessment (OTA) and the National Institute of Mental Health 19
10 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

(NIMH) focused on data characterizing the inheritance of Alzheimer’s disease, schizophrenia,

major mood disorders, panic disorder, and obsessive-compulsive disorder. Following an overview

of some basic genetic concepts and research techniques, this chapter summarizes what we know

about the inheritance of these mental disorders. 1

GENETIC RESEARCH PRIMER

Although molecular genetics and the search for

specific genes have upstaged other approaches,

classical research methods—family studies, twin

studies, and adoption studies—are the mainstay of

mental disorders genetics (table 2-1) (box 2-l).

Characterization of the prevalence and pattern of

traits among related individuals helps illuminate

their genetic basis, addressing the following questions: Are these traits inherited? What is the relative contribution of genetic versus nongenetic

factors? What is the pattern of inheritance? The

genetic bottom line—the relative influence of inherited factors-merge from these classical

studies.

Classical genetic studies are critical for understanding the inheritance of a trait or disorder; they

cannot locate or characterize specific genes. For

this reason, as well as technological advances,

linkage analysis has become the lodestar of mental disorders genetics. By investigating the distribution of DNA markers and disorders among

family members, linkage analysis provides a

method for identifying the location of disease

genes. Linkage analysis can determine whether a

single gene makes a major contribution to a trait

and where that gene is located. Based on knowledge of the chromosome location, researchers can

narrow in on a gene in a process known as positional cloning. Where little knowledge of the underlying cause or molecular mechanism of action

in a disorder exists—as is the case in most mental

disorders—linkage analysis is especially appealing. However, a variety of factors complicate linkage analysis of many mental disorders, including

the likely involvement of multiple causes, their

complex patterns of inheritance, and uncertainty

as to what is inherited and how (see references

54,64 for detailed discussion). Thus, alternative

methods for finding genes associated with mental

disorder are of interest.

The sib pair method can be used in the search

for genes linked to mental disorders. This approach is based on the premise that if a genetic

marker and a trait (a disease or biological marker,

for instance) are linked, pairs of siblings (or other

affected relative pairs) who share a trait will be

more likely to have the same genetic marker than

would be expected by chance. The sib pair method

offers some significant advantages in mental disorders research: it does not require prior knowledge of how a trait is inherited—which is

generally lacking in mental disorders—and it does

not require large, multigenerational families with

many afflicted members-which are relatively

difficult to locate in mental disorders (40,54). The

robustness in detecting linkage in the face of ignorance of the genetic mode of transmission comes

with a price, however: less sensitivity. That is, it

may fail to detect a linked gene. Furthermore, the

sib pair method still requires a gene that has a large

effect on a condition.

Association studies offer another approach to

identifying genes that influence mental disorders.

This method examines gene variation and disease

in patient samples and controls. Important for behavioral traits in general and perhaps mental disorders specifically, association studies can detect

genes playing a minor role in a disorder. Association studies are most useful when candidate

genes—genes suspected a priori of playing a role

in a condition—are available; systematic search

for association throughout the genome is not yet
Chapter2 Research Results 111

Type of study Definition Information that may be derived Limits of approach

Family Consider whether a trait runs in Showing that a trait is more

studies a family. prevalent among relatives of

an affected individual than in

a control population suggests

the importance of genetic

factors.

● The observation that a trait is

more common among first-degree relatives-parents, siblings, and offspring-than

more distant ones is consistent with a genetic hypothesis.

● The way in which a trait is distributed among family members may also elucidate the

mode of inheritance.

Twin studies Compare how often identical ● A higher concordance rate for

twins, who are genetically iden- a trait among identical twins

tical, and fraternal twins, who versus fraternal twins usually

have the genetic similarity of demonstrates a genetic basis

nontwin siblings, are similar, or for the trait.

concordant, for a trait. ● The absence of 100 percent

concordance among identical

twins shows that nongenetic

factors also play a role in producing the trait.

● Showing the familial nature of a

trait is necessary but not sufficient for proving it is inherited;

such data do not conclusively

demonstrate the genetic basis

of a trait, since family members share not only genes but

also their environment.

● Raise issues around the way in

which twins are sampled; the

assumption that identical and

fraternal twins experience the

environment identically; the

definition of concordance; and

the statistical methods for

measuring concordance.

Adoption Focus on adopted individuals

studies and their adoptive and biological families. In three commonly

used research designs:

● the adopted away offspring of

affected parents are studied

and compared with control

adoptees of normal parents; or

■ the index cases are adopted

people who have developed

a disorder of interest; the

rates of illness are then

compared in their biological

and adoptive relatives; or

■ least commonly, the rate of illness in adoptees who have

affected biological parents

but who were raised by unaffected adoptive parents, are

compared with the rates of illness in the offspring of normal parents brought up by

adoptive parents who themselves become affected.

●

■

Attempt to disentangle the in- ● Generally, do not rule out the

fluence of genes from that of effect of nongenetic factors

the environment. preceding adoption, such as

Can provide powerful evi- possible prenatal influences.

dence of a genetic effect.

SOURCES’ P. McGuffin, M.J Owen, MC O’Donovan et al., Seminars in Psychiatric Genetics (London, England: Gaskell, 1994), US Congress, Office of Technology Assessment, The Biology of Mental Disorders, OTA-BA-538 (Washington, DC: US. Government Printing Off Ice, September 1992).
12 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Candidate gene. A gene whose involvement in a trait or disease is suspected before linkage analysis or

other gene-searching techniques are applied.

Chromosome. As seen under a microscope, threadlike structures within the cell. Each chromosome consists of a of linear DNA (deoxyribonucleic acid) molecule.

Chromosome banding pattern. A pattern of alternating dark and light transverse regions (bands) formed

on a chromosome by chemical treatment and staining. The different bands along a single chromosome are

used to identify different regions of the chromosome.

DNA (deoxyribonucleic acid). A doubled stranded molecule consisting of four deoxyribonucleotide or,

more simply, base pairs. Species-specific and individual-specific genetic information is encoded in the

order of the base pairs along the chromosomal DNA molecule,

DNA markers. Variations in DNA sequences of known chromosomal location, including restriction-fragment-length polymorphisms (RFLPs) and microsatellite repeat markers. While a DNA marker may not be

part of a gene causing a particular disorder, it can be useful in determining a disease gene’s location, DNA

markers also can be used for genetic testing.

Gene. A length of DNA that specifies the structure of a particular protein product. Genes are arranged

along the chromosomes in a linear order, with each having a precise position or /ecus. Alternative forms of

a gene that can occupy the same locus are termed a//e/es. Each chromosome bears only a single allele at

a given locus, though in the population as a whole there may be many alleles, any one of which can

occupy that locus.

Genome. The totality of the DNA contained within the chromosome set of a species. The human genome,

for example, consists of approximately 6 billion base pairs of DNA distributed among 46 chromosomes.

Molecular genetics. The study of the molecular details of the regulated flow of genetic information among

DNA and proteins from generation to generation,

Mutation. Any alteration in the base sequence(s) of the constituent DNA molecule(s) of the genome of an

organism.

Positional cloning. Describes a set of techniques by which disease genes are identified through their

position in the genome rather than through their function. In its initial stages, this approach can rely upon a

systematic search of the genome for linkage, This has been made possible by the availability of systematically constructed linkage maps of the human genome. These consist of DNA markers whose chromosomal

positions have been mapped, which are polymorphic and which have been assembled so that they are

approximately evenly spaced throughout the genome.

SOURCES P McGuffin, M J Owen, M C O’Donovan, et al , Seminars Psychiatric Genetics (London, England: Gaskell, 1994), U S

Department of Energy, Los Alamos Science, The Human Genome Project, Number 20, 1992.

useful. Unfortunately, few candidate genes exist progressively deteriorating course of Alzheimer’s

for mental disorders at the present time. disease (AD). In the six- to 20-year span of the

disease, people suffer increasing memory loss,

ALZHEIMER’S DISEASE confusion, and disorientation, and may exhibit

Loss of memory for recent events, seemingly be- other symptoms—such as paranoia, irritability,

nign forgetfulness, marks the beginning of the combativeness, restlessness, fearfulness, and
Chapter 2 Research Results 113

problems with language—until they are incontinent, bedridden, and unable to speak or eat. Usually a disease of elderly people, AD afflicts an

estimated 5 percent of people over 65 and approximately 20 percent of those over the age of 80.

Much less commonly, AD afflicts people who are

younger, in their 40s and 50s.

There is no cure for AD or treatment useful for

most patients. The pathology of AD is well characterized: extensive nerve cell loss in some regions of the brain, accumulations of twisted

protein filaments inside nerve cells—neurofibrillary tangles—and abnormal clusters of degenerating nerve cell fibers, other brain cells, and a

protein called B-amyloid—neuritic plaques. Despite significant research advances in the last 10

years, which increasingly reveal pieces of the etiologic puzzle, the triggers for this neurological catastrophe remain unknown.

Advances in molecular genetics offer important clues about the origins of AD (7,40,57).

These advances have not come without difficulty,

nor without surprise, as suggested by the genetic

epidemiology of the disease. Family studies show

a threefold increase of AD among first-degree relatives of afflicted individuals, especially those

with an early onset of symptoms. Indeed, data indicate that a few rare forms of AD, mostly with

early onset, are produced by a single gene. Of

course, most cases of AD do not have an early onset, and the pattern of inheritance is less clear for

the more common mid- and late-onset disorder.

Part of the problem is determining the family distribution of such a late-onset disease; many family

members may succumb to other causes before developing AD. Some hypothesize that what is inherited is not AD per se, but the timing of its onset.

Also, both genes and nongenetic factors are

thought to play a role.

Two research findings initially propelled molecular genetic research of Alzheimer’s disease.

First, the gene for a precursor to 13-amyloid, a protein concentrated in the brains of people with AD,

was found; the gene mapped to a region of

chromosome 21, which is associated with Down’s

syndrome (figure 2-1). Second, linkage analysis

located a gene for AD in the same region. Indeed,

Chromosome 14 Chromosome 19 Chromosome 21

n 13.3

 11.1

11.1

13 11.2

21

22.1

HspA2 22.2

22.3

Chromosomes 14, 19, and 21 are depicted, with banding

patterns identified on the right side of each chromosome. The

locations of markers and genes that have been reported to

be linked to AJzheimer’s disease are on the left. FAD region

indicates the region on chromosome 14 containing the AD

locus.

KEY: HspA2 = heat shock protein A2, Apo E = apolipoproteln E: APP =

13-amyloid precursor protein

SOURCE: R.F. Clark and A.M. Goate, “Molecular Genetics of Alzhelmer’s Disease, ” Archives of Neurology 501164-1172, 1993

researchers were long aware of the link between

AD and Down’s syndrome: all people with

Down’s syndrome ultimately show brain changes

typical of AD.

The intensive investigation that ensued unfortunately turned out mostly negative or at least confusing data. A role for the 13-amyloid precursor

protein gene in AD was supported by data from

some linkage studies, and specific mutations in

the gene have since been found. One study linked

a mutation in this gene to an inherited form of cerebral hemorrhage. But many studies did not replicate the linkage between AD and the 13-amyloid

precursor protein gene. Ultimately, researchers

agreed that while the 13-amyloid precursor protein
14 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

gene is associated with AD, it accounts for only a

very small proportion of the early-onset cases.

Most AD is caused by something else. That

should not diminish the importance of this result.

This discovery has implications for our basic understanding of AD. First, the data from molecular

genetics suggest that 13-amyloid protein may be

more than just a correlated factor with AD; it may

cause AD, a hypothesis under intensive investigation. Second, mutations to this gene lead to AD

and recurrent stroke, evidence that these two clinical conditions are not distinct, but rather different

results of the same gene defect.

Nonetheless, the vast majority of AD cases are

not explained by mutation of the 13-amyloid protein precursor gene located on chromosome 21. A

genomewide search thus ensued for other genes

linked to early-onset AD. Evidence for such a

gene on chromosome 14 soon emerged. With

quick replication, even among some families

where the chromosome 21 site had been implicated previously, it became clear that a gene on

chromosome 14 is responsible for a majority of

(but not all) early-onset AD cases. Currently, researchers worldwide are pursuing intensively the

chromosome 14 AD gene.

As noted, evidence points to etiologic heterogeneity—the involvement of more than one gene

as well as nongenetic factors—in late-onset AD.

But recent and surprising discoveries point to the

important action of a gene on chromosome 19 in

late-onset AD. Replicated data link a particular

version of a chromosome 19 gene coding for apolipoprotein E—the e4 allele—to AD. How this

protein may lead to AD is not known: studies

show that apolipoprotein E plays a role in fat metabolism, cell injury repair, and cell growth, and is

a constituent of amyloid plaques and neurofibrillary tangles in AD. Nor does apolipoprotein E appear to play a role in all late-onset AD; by current

estimates, approximately 50 percent of all cases

do not possess the e4 allele.

Despite the obstacles-difficulties in performiing family studies among an elderly population

and the likely interplay of a variety of causative

and modulating factors—researchers have

learned a great deal about the molecular genetics

of AD. The discovery of some of the genes that

may be involved in AD suggests brain mechanisms that underlie this disease. These findings

also offer clues about how AD relates to other illnesses. These data offer considerable promise that

we will understand the cause of AD, will be better

able to diagnosis it, and perhaps can develop treatments for and ultimately preventive interventions

against its devastating effects.

SCHIZOPHRENIA

For many, the term schizophrenia is synonymous

with severe mental illness. It assails an individual thought processes, perceptions, emotions, and

behavior. Thought and perceptual disturbances

are the hallmark of schizophrenia. Components of

thought may become dissociated or fragmented

and the flow of thought interrupted. The ability to

concentrate and focus attention is impaired. Individuals with schizophrenia commonly experience

delusions and hallucinations. Nearly one in every

100 American adults will develop schizophrenia

during the course of his or her lifetime. The disease’s symptoms typically emerge during the late

teens and 20s, with the majority of individuals

suffering an intermittent but lifelong course. Currently, there is no way to prevent or cure schizophrenia; although, medications are available that

can control some symptoms for many patients.

For nearly a century, researchers have explored

the role of genes in schizophrenia (reviewed in

20,21,30,40,64). Though questioned because of

several methodological weaknesses (e.g., knowledge of the diagnostic status of family members

could have made researchers less objective, diagnoses often were based on hospital records or

third-party interview rather than direct observation, and the criteria for diagnosis were not clearly

enumerated), early family studies demonstrated

that schizophrenia runs in families, and twin studies support the role of genes. Using more stringent

protocols and procedures, more recent family,

twin, and adoption studies confirm these earlier

results.

Undoubtedly, schizophrenia runs in families.

Of the more than 40 systematic family and twin
Chapter 2 Research Results 115

Identical twins Fraternal twins

Number of Concordance Concordance

Study pairs rate (percent) Pairs rate (percent)

Finland 1963, 1971 17 35% 2 0 1 3 %

Norway, 1967 55 45 9 0 15

Denmark, 1973 21 56 41 27

United Kingdom,

1968, 1987 22 58 33 15

Norway, 1991 31 48 28

United States, 1969,

4

1983 164 31 268 6

Pooled concordance

Median 310 46 480 14

Weighted mean 39 10

aData from newer twin studies, using probanwise concordance rates.

SOURCE. I I Gottesman, Schizophrenia Genesis; The Origins Madness (New York, NY: W H. Freeman, 1991), I I

Gottesman, "Schizophreia,” Seminars in Psychiatric Genetics, P, McGuffin, M.J. Owen, M.C O’Donovan, et al. (eds.)

(London, England Gaskell, 1994)

studies, all show increased rates of schizophrenia

among family members versus rates in the general

public. First-degree relatives of an individual with

schizophrenia have approximately 10 times the

general risk of developing the disorder.

Of course, just because a trait runs in families

does not necessarily implicate genes as the cause.

Data from twin and adoption studies, however, do

strongly support a role for inherited factors in

schizophrenia. Although estimates vary, depending on the statistical method used and the sample

population, data consistently show that a person

whose identical twin has schizophrenia is at higher risk for this condition than a person whose fraternal twin has the disorder (table 2-2). To be

precise, six modem studies in the literature and a

seventh ongoing in Nagasaki, Japan, show increased concordance among identical versus fraternal twins (22). Similarly, replicated data from

adoption studies indicate that schizophrenia runs

in biological but not adoptive families (58). Data

recently reported from a nationwide study in Denmark expand on this observation: schizophrenia

was found exclusively among biological relatives, with a ten times greater prevalence than in

the biological relatives of controls (31,37).

The discussion thus far yields too simplistic a

view of the genetics of schizophrenia. Even as

data from nearly a century of research consistently

point to genetic factors in schizophrenia, its complexity is also an undeviating observation. The

very presentation of the disorder is complicated.

Symptoms vary widely among individuals, combining in different ways, and changing over time.

This variability has raised questions about how to

conceptualize schizophrenia: Is it a single disorder? A group of disorders? A conglomerate of several disease processes? What is its relationship to

other mental disorders?

The clinical presentation of schizophrenia has

raised questions for geneticists. What in fact

would a schizophrenia gene or genes result in?

Hypotheses include: schizophrenia alone; schizophrenia and mood disorders; schizophrenia and

any mental or substance abuse disorder; schizophrenia and some types of abnormal personality

traits and disorders; psychosis; or other traits such

as problems with eye movements. More work is
16 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

needed to definitively prove any of these hypotheses (62).

Not only is schizophrenia’s relationship to other disorders and traits complex and somewhat obscure, but data concerning its inheritance are

equally confounding. The way inherited factors

may express themselves within families remains

unknown. The distribution of schizophrenia within families is not consistent with any simple pattern of inheritance. Studies generally rule out the

action of a single gene without determining

whether a couple of genes, or many, are important

in producing schizophrenia.

While classic genetic studies support a role for

genes in schizophrenia, they also circumscribe

how big a role inherited factors might play. Because an identical twin of someone with schizophrenia exhibits the disorder approximately 30 to

60 percent of the time, nongenetic factors must

also be important (61). Such discordance among

identical twins does not necessarily mean, however, that nongenetic factors are the cause of

schizophrenia in the affected twin. The unaffected

twin simply may not express the genetic factors

that both twins have. Evidence for this interpretation emerges from a followup and expansion on a

Danish twin study (23). The researchers found

that the risk of schizophrenia to the children of unaffected twins equaled that of the affected twins’

offspring.

Researchers recently applied the tools of molecular genetics and linkage analysis to probe the

inheritance of schizophrenia. A report that an uncle and nephew with schizophrenia shared a

chromosome defect—an extra copy of part of

chromosome 5—prompted linkage analysis using

markers on this chromosome (4). Support for such

linkage soon emerged from a study of seven British and Icelandic families (56). However, a simultaneously reported study in a separate extended

family in Sweden ruled out this linkage (36). Subsequent studies have since rejected a link between

genes on chromosome 5 and schizophrenia (30,

64).

Crow and colleagues (12) have proposed that

the pseudo-autosomal region of the X and Y

chromosomes contains a schizophrenia gene. The

pseudoautosomal region is a small portion of the

X and Y chromosomes. When genes located in

this region are inherited from the paternal side, affected offspring will be the same sex more often

than expected by chance. Such a pattern of inheritance does occur in schizophrenia. Furthermore,

data from a sib pair analysis offers support for this

hypothesis (9), although other data are not consistent with linkage to this region of the X and Y

chromosomes (3,47). More recent work suggests

linkage to a gene on the X and Y chromosomes

outside of the pseudoautosomal region (13,16).

Another series of recent linkage studies implicate a gene on chromosome 22. Pulver and colleagues (51) reported a potential linkage to this

chromosome. The finding was not statistically

significant but might have indicated a gene that

accounted for only a small proportion of the cases

of schizophrenia. Two other groups found evidence consistent with this finding (10,49). However, a second sample reported by Pulver and

colleagues (50) excluded linkage to a site on

chromosome 22.

Unlike AD, the complexities of diagnosis and

family aggregation, as well as its relationship to

other traits and disorders and the multiplicity of

causative factors likely involved, have made

schizophrenia elusive prey for the molecular geneticist. That schizophrenia runs in families and

that genes play a role are strongly supported by

many sources of data. The nature of the genetic

contribution is far from clear. Furthermore, although some studies hint at “genetic” forms of

schizophrenia, to date nothing sets apart a subgroup of schizophrenia as obviously produced by

a single gene (15). Finally, although there have

been occasional reports of linkage between

schizophrenia and various chromosome markers—including protein-based markers such as

blood proteins, DNA markers, and various candidate genes—researchers have yet to confirm the

location or identity of a schizophrenia gene. A

leading genetic researcher recently commented on

these difficulties, contemplating the implications

for future research (62):
Chapter 2 Research Results 117

Why has the genetic epidemiologic trail for

schizophrenia not led to a clear genetic mechanism? It may be that our initial expectations

were too high. Unlike familial Alzheimer’s disease, schizophrenia does not show a clear mechanism of transmission. Nor does it have an

unambiguous pathophysiological signature. It is

tempting to appeal to genetic heterogeneity, but

heterogeneity has not stymied research in Alzheimer’s disease. Unless schizophrenia is extremely heterogeneous, why is it so difficult to

find schizophrenia genes? Some see a multifactorial explanation that posits the accumulation

of many genetic and environmental risk factors

as the cause of schizophrenia. This hypothesis

has much merit but presages a long journey

along the epidemiologic trail if “many” turns

out to be a large number.

MAJOR MOOD DISORDERS

Data from a recent, large epidemiologic study

show that in a given year nearly 5 percent of

American adults—including twice as many

women as men—will experience an episode of

major depression (65). Interest or pleasure in activities will dissipate, sleep and appetite are affected, and sense of worth and the ability to

concentrate typically decline. Suicide stands as a

very real threat. Nearly 1 percent of the population

will cycle between such bouts of depression and

manic illness, with its extremely elevated mood

and self-esteem, reduced need for sleep, abounding energy, racing thoughts, unrestrained activity

and talk, and even psychosis. Although treatments

effective for many people with major depression

or manic-depressive illness (also called bipolar

disorder) are available, no cure exists.

The concentration of mood disorders in families has long been recognized (19,35,40,41,63,

64,65). Data consistently show that the parents,

siblings, and children of people with bipolar disorder or major depression are at a much greater

risk than the general population. Twin studies corroborate this observation, pointing to a role for inherited factors. For example, data show that the

identical twin of an individual with bipolar disorder would exhibit that disorder three times more

often than would a fraternal twin (figure 2-2).

0.80

0.65

Any mood Bipolar Severe Depressionb

disorder disorder depression

 Identical twins Fraternal twins

Graphically depicted data were derived from evaluation of

110 pairs of twins. Identical twins shared mood disorders,

especially biopolar disorder, more frequently than fraternal

twins.

a Three or more epsodes of depression

b Less than three episodes of depression

SOURCE: Adapted from A. Bertelsen, B Harvald, and M. Hauge, “A

Danish TwinStudy of Manic-Depresswe Disorders, ” British Journal of

Psychiatry 130.330-351, 1977

Similar replicated results can be found in 11 independent twin studies of mood disorders (22).

Family and twin studies provide strong and

consistent evidence that genes contribute to major

mood disorders. But as is the case with AD and

schizophrenia, details from the research tell a

complicated story: concordance rates for bipolar

disorder and major depression among twins vary

considerably between studies reflecting among

other things the use of different diagnostic categories and methods. Although data from adoption

studies generally support a role for genetics, they

are not completely consistent. Research focused

on milder forms of depression, and not bipolar
18 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

disorder, provides even more ambiguous results

concerning the role of inheritance. And studies of

how major mood disorders are distributed within

families do not divulge the kind of genetic mechanisms that may be involved (e.g., a single gene).

The relationship between bipolar disorder and

the spectrum of depressive illnesses, as well as

other disorders and personality traits, presents further uncertainty. Considerable evidence from

studies evaluating family history, clinical symptoms and course, response to pharmacological

treatment, and other factors distinguishes bipolar

disorder from major depression. But the separation is not complete. Family and twin studies suggest at least a partial genetic connection between

major depression and bipolar disorder. For example, identical twins who both have a mood disorder not infrequently have different forms.

Similarly, first-degree relatives of a person with

bipolar disorder are at greater risk of developing

any mood disorder than the general population.

Questions about the nature of depression are

even more difficult to answer. Is depression a

single disorder or a class of disorders? How are

less severe episodes of depression and other mental disorders related to major depression? Because

depression varies considerably in its course,

symptoms, severity, and association with other

disorders, some believe that depressive disorders

may differ in kind as well as degree-that depression is heterogeneous. However, other data from

family histories and longitudinal studies provide

evidence that depression may constitute a continuum from “the blues” to severe depression. The

heritability of depression appears to be correlated

with the severity of the condition. Recurring bouts

of depression appear to be more heritable than a

single episode. Also, major depression that has an

earlier age of onset maybe more heritable. A variety of data point to a genetic relationship between

depression and other conditions as well. Certainly

there is high comorbidity between depression and

substance abuse and anxiety disorders (2,32,33,

60,67,69). For example, a recent large study of

twins found that various personality traits-emotional instability, vulnerability to stress, and

anxiety-proneness-appear to be connected to depression, largely as the result of genetic factors according to the study’s authors (33).

Many studies have attempted to locate specific

genes that lead to mood disorders, with initial reports of positive findings on the X chromosome

and chromosome 11 receiving the most publicity.

More recently, data suggest that a gene on

chromosome 18 is linked to susceptibility to

mood disorders (5). However, none of these results, nor any other, have been consistently confirmed. As the first modem linkage study for a

mental disorder receiving intense publicity but

later being retracted, the search for a mood disorder gene on chromosome 11 bears retelling.

The scientific and popular press heralded a report linking mood disorders to chromosome 11

among a group of Amish families in Pennsylvania

(18). The Amish are an ideal population for studying the genetics of all kinds of disorders, especially mental disorders. They are the progeny of a

small group of people who emigrated from Europe in the early 18th century. Since they seldom

marry outside their own community, they have

preserved a relatively homogeneous genetic heritage. Also, due to their religious convictions, they

forswear the use of drugs and alcohol, abuse of

which may confound the diagnosis of mood

disorders.

The results of the Amish study conflicted with

two reports on non-Amish families published

about the same time (17,27). These studies ruled

out linkage of mood disorders to chromosome 11

in nine families. Furthermore, results from a followup study of the same Amish families two years

later disputed the original findings (29). The reanalysis, which included new family members

and a change of diagnosis in two individuals due

to the subsequent onset of mood disorders, also

excluded the gene on chromosome 11 as the cause

of all cases of mood disorders in the Amish

families.

How can we summarize the current status of research into the genetics of mood disorders? As

with schizophrenia, data converge on the conclusion that genes play a role in mood disorders, especially bipolar disorder and more severe forms of

depression. But the nature of this inheritance is
Chapter 2 Research Results 119

Lifetime prevalence rates of panic disorder

in first-degree relatives (percent)

Proband diagnosis Panic disorder Control

Direct interview studies

Harris et al., 1983

Crowe et al., 1983

Noyes et al., 1986

Weissman et al., 1993

Mendlewicz et al., in press

Maier et al., 1993

Family history studies

Moran and Andrews, 1985

Hopper et al., 1987

20.5% 4.2%

17,3 1.8

14.9 3.5

14.2 0.8

13.2 0 . 9

7,7 1.5

12.5

11.6

SOURCE: M M Weissman, “Family Genetic Studies of Panic Disorder,” Joumal of Psychiatric Research, (Suppl.)

27:69-78, 1993.

obscured by sometimes diverse research results,

an uncertain mode of transmission, and the high

prevalence of depressive disorders. Furthermore,

the application of molecular genetics to mood disorders has yet to yield a confined, positive result.

PANIC DISORDER

The hallmark symptom of panic disorder is a sudden, inexplicable attack of intense fear that is

associated with powerful physical symptoms

(44,64,68). In just a few minutes, an extreme

sense of fear overtakes an individual, his or her

heart begins racing, he or she starts to perspire—

sometimes profusely—and he or she has trouble

breathing. A single attack is shortlived, lasting

about 10 minutes. These symptoms often leave a

patient believing that he or she is suffering from a

heart attack or is losing his or her mind. Some patients go to the emergency room in the belief that

they are about to die from a heart attack. In fact,

many individuals with panic disorder seek general

medical professional care at an increased rate.

Panic attacks occur about two times a week, although the frequency varies considerably among

individuals. One person’s panic attacks may be

rare, having little effect on his or her functioning,

while another’s panic attacks and accompanying

anxiety may be so intense that he or she remains

completely sequestered at home, a condition

known as agoraphobia. Although not completely

effective, treatment of panic disorder with medication or psychotherapy, or both, often appears

helpful. Data show that approximately one to two

persons in 100 will develop panic disorder during

their lifetime, with women being twice as likely to

develop it as men. Another 3.6 percent of the population suffer repeated panic attacks, without

meeting the criteria for full-blown panic disorder.

A major shift in the categorization of panic disorder occurred in 1980. It was distinguished from

general forms of anxiety (34,38,40,66,70). While

research data generally support this distinction, it

means that few studies preceding the reclassification address the inheritance of panic disorder specifically. At least eight family studies have been

completed using the modern definition of panic

disorder (table 2-3). Even these modem studies

are not uniform in their methodology, diagnostic

classification, or estimates. But all point to higher

rates of panic disorder among first-degree rela-
20 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

tives of individuals with this condition when

compared with the general population or control

groups. Furthermore, data from one of the family

studies (46) show a familial link between panic

disorder and agoraphobia. Family studies subjected to statistical analyses have not demonstrated the way in which panic disorder might be

inherited: a single gene with incomplete penetrance could explain the pattern of disorder seen in

families, or several genes plus nongenetic factors

may be at play. The family studies do suggest that

more severe forms of the condition aggregate in

families.

No adoption studies focus on panic disorder;

however, data from three twin studies shed light

on this condition. All of the twin studies point to a

relatively modest role for genes in panic disorder.

One small study found only a 31 percent concordance rate among the 13 pairs of identical twins

and no concordance among the 16 pairs of fraternal twins examined, a rate lower than family studies predict (60). In 446 pairs of twins, concordance

rates for panic disorder were not significantly different among identical and fraternal twins (l). A

substantial increase in concordance rates among

the identical twins emerged when all anxiety disorders were included in the estimate, leading the

authors to hypothesize that genes relate to a general risk of anxiety. Another large twin study found

only a modest increase in panic disorder among

identical versus fraternal twins (34). The study’s

authors concluded, in concert with data from the

other twin and family studies, that genes appear to

play a smaller role in less severe cases.

The data from genetic studies of panic disorder,

although more limited than the other mental disorders discussed so far in this chapter, reveal similar

trends: panic disorder runs in families and genes

seem to play some role; however, there are fewer

data, which are much less consistent. Linkage

studies of panic disorder are currently in progress,

but no evidence at yet links this condition to the

action of a major gene.

OBSESSIVE-COMPULSIVE DISORDER

Obsessive-compulsive disorder (OCD) is characterized by recurrent and persistent thoughts,

images, or ideas-obsessions-and stereotypic,

repetitive, and purposeful actions-compulsions

(64). Individuals with OCD cannot resist these

persistent ideas or impulses, although they view

them as irrational and unwanted. One common

manifestation of this disorder is the obsessive

feeling of being dirty or contaminated, which

leads to the compulsion of repeated hand-washing. Hand-washing may be so frequent that the

skin is rubbed raw. Another common obsession is

excessive doubt, which leads to compulsive

checking. Although long thought to be resistant to

treatment, research has led to medications and

psychotherapy that offer considerable therapeutic

benefit.

Recent epidemiologic data indicate that OCD,

once thought to be quite rare, afflicts approximately 2.6 percent of the U.S. population at some

time during their lives. Men and women appear to

be afflicted equally, although OCD may be slightly more common among women. The symptoms

begin in childhood or adolescence in one-third to

one-half of the individuals who develop the disorder. The average age of onset is 20.

Few family and twin studies using modem

diagnostic criteria and methodologies have assessed the distribution of OCD in families and the

role of genetic factors in this condition. There are

no published adoption studies. What do we know

from existing data? Although fraught with methodological shortcomings, including unclear

methods for diagnosing OCD, no direct interviews conducted to make diagnosis, and no control groups, most studies conducted before 1970

found that symptoms of OCD tend to run in families (2,52). Several recent family studies have

used standard diagnostic criteria and direct structured interviews of subjects and their family members and most evidenced a familial basis for OCD.
Chapter 2 Research Results 121

These recent family studies are not unproblematic, however. Several of the studies lacked control

groups. Not all of them reported increased OCD

among family members of those afflicted by

OCD. The rates of OCD among family members

varied considerably. There are two other family

studies of OCD and Tourette’s syndrome, which

implicate a link between these conditions, at least

in some families (24,48).

Data from existing twin studies also paint a

complicated picture. In 1986, Rasmussen and

Tsuang published a review of previous twin studies of OCD (53). They calculated an overall concordance rate of 63 percent for identical twins.

This high concordance rate must be interpreted

conservatively since most of the included data

were from single-case reports with no control

groups or fraternal twin estimates. Other twin

studies with data on OCD focused on a variety of

symptoms in anxiety disorders (1,6,8,59). In general, these studies did not find much higher rates

of OCD in identical versus fraternal twins. Rather,

most of these studies signal a genetic component

underlying nonspecific symptoms of anxiety.

In summary, existing data do not unambiguously support a significant role for genetic factors

in OCD. Further study, using sound methods, is

needed to resolve any role that genes play in OCD.

Attention to the spectrum of possible disorders

that may be inherited, including OCD, symptoms

of other anxiety disorders, and Tourette’s syndrome, is also warranted.

SUMMARY AND CONCLUSIONS

Studies have characterized the familial nature of

the disorders considered in this chapter. Data consistently point to the role of inherited factors in

Alzheimer’s disease, schizophrenia, and major

mood disorders. Furthermore, researchers have

located and in some cases identified specific genes

involved in Alzheimer’s disease. No replicated

positive findings have yet emerged from efforts to

locate individual genes associated with any other

mental disorder considered in this chapter. And

data also show that nongenetic factors contribute

to these conditions.

The immediate clinical implications of genetic

research of mental disorders are quite limited. Genetic tests to improve diagnosis are not yet available, nor are new treatment approaches. In

general, there are enough data to give family

members some information about empirical

risk—the probability of developing a related

condition. The important caveat here is that such

information is not specific to a particular individual or family and thus may be difficult to interpret

(see chapter 3).

The limited clinical application of data from

genetic studies of mental disorders by no means

impugns the relevance of this research. Indeed, in

AD the research advances have been quite remarkable. The complexity of major mental disorders

and genetics predicts a slow accumulation of

knowledge (box 2-2), as noted by one workshop

participant (55):

We don’t fully understand the genetics of the

disorders. We don’t have very strong evidence

beforehand about how many genes are involved,

or how difficult the problem is going to be. It’s

hard to say to the public what the answer is going

to be because we really don’t know ourselves.

It’s something we’re going to have to live with, I

think, for a number of years until it all gets

sorted out.

Several factors justify continued research into

the genetics of mental disorders: inherited factors

contribute to at least a subset of major mental disorders. Rapid advances in molecular genetics

make this a powerful technology. For many conditions, genetic approaches offer the most important

lead for understanding their biological underpinnings. Ultimately, information about the molecular genetics of mental disorders may lead to

improved diagnosis and treatment. Finding causative or contributing genes may be the key to rational design of new drugs and therapeutic

advances. Alzheimer’s disease provides an encouraging example, with the location of genetic

culprits being found even in the late-onset form of

the disorder, which is common and complex like

the other mental disorders considered in this

report.
22 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

In terms of genetics, Huntington’s disease (HD) could not be more different from the mental disorders

discussed in this chapter. The pattern of HD inheritance is simple: every individual who receives a single

copy of the HD gene will develop HD, Despite the apparent straightforward genetics, quest for the HD

gene proved unexpectedly prolonged and torturous, evincing the unpredictable path of research as well as

the many mysteries of genetics that remain. Herein lies a lesson for mental disorders genetics.

Our story begins with an incredible stroke of good fortune. Using the nascent technology of linkage

analysis with RFLPs, the HD gene was located on chromosome 4 in 1983, As the first disease gene located

using this approach, the finding launched an era of disease gene searches, including genes linked to mental disorders. It also inspired near elation among individuals with HD and their families. Despite knowledge

of the pattern of inheritance and the brain degeneration involved in HD, there was no cure for this terrible

disease, no way to prevent it, nor even an effective treatment. Manifesting in midlife, body movement and

mental functions are profoundly affected in HD. Over the course of 10 to 20 years, individuals with HD

suffer the progressive loss of muscular control, resulting in terrible jerking of limbs, abnormal posture and

speech, impulsiveness, psychosis, wild mood swings, and ultimately complete incapacitation, immobility,

and death.

Knowledge of the HD gene location had a near-immediate clinical impact. A genetic test for the disease

was developed. But it was the prospects for actually isolating the gene, understanding its structure, and

the protein for which it coded that spurred an intensive research effort. With a historic collaboration in

place, researchers probed the tail end of chromosome 4, isolating various markers for the region, mapping

intimate details of its physical and chemical structure, assessing subtle changes in chromosome structure

among individuals with HD and their families, and testing the potential role of genes known to be located at

this site. But year after year passed without the successful isolation of the HD gene. It took a decade and

the efforts of many scientists for this goal to be realized.

It turns out that the genetic mechanism involved in HD-this so-called simple and straightforward genetic disease-was new to researchers. Instead of some static alteration in the DNA code that is passed

unchanged from generation to generation, the HD mutation involves an unstable DNA sequence, repeated

many times, the number of copies changing as it is transmitted from parent to offspring. This novel mechanism, eluding researchers for so long, explained characteristics of HD that previously had not made sense.

Clinicians and scientists had observed rare cases of HD emerging in childhood and adolescence; almost

always such juvenile onset resulted from paternal inheritance, We now know that a large increase in the

number of copies of the DNA sequence involved in HD correlates to a younger age of onset. The longest

repeats result from male transmission.

The type of mutation underlying HD has been found in a number of genetic disorders, including Fragile

X syndrome, spinobulbar muscular atrophy, and myotonic dystrophy. In fact, a variety of new genetic

mechanisms that are linked to disease are being uncovered, Thus, we are only beginning to understand

the human genome and genetic mechanisms involved in disease. For the study of mental disorders, this

humbling realization urges patience and steadfastness. Researchers not only have to contend with the

many uncertainties and complexities of mental disorders, but also the limits of our knowledge of human

genetics.

SOURCES J F. Gusella, M.E. MacDonald, C.M. Ambrose, et al., “Molecular Genetics of Huntington’s Disease, ’’Archives of Neurology

501157-1153, 1993; J.F. Gusella, NS. Wexler, P.M. Conneally, et al., “APolymorphic DNA Marker Genetically Linked to Huntington’s

Disease, ” Nature 308:234-238, 1983; The Huntington’s Disease Collaborative Research Group, “A Novel Gene Containing a Trinucleotide Repeat That Is Expanded and Unstable on Huntington’s Disease Chromosomes,” Cc// 72:971-983, 1993.
Chapter 2 Research Results 123

With research being an imperative for achiev- genes, 2) verification of a positive finding can be

ing a better understanding of these conditions, the obtained quickly, and 3) finding a gene relevant in

question becomes: what kind of research? Unfor- only a few large families will teach us something

tunately, there is no single or simple answer to this about the biology of a condition (11). Kendler and

question. For conditions in which a major gene Diehl offer the following rationale for schizophreappears to be at the root, such as early-onset AD, nia, which may well apply to other mental disorthe application of molecular genetics, including ders (30):

linkage analysis and positional cloning, has and

continues to offer great promise. For conditions in

which the contribution of inherited factors is not

clear, such as in OCD, continued probing of the

role of genetics, using family and twin studies, is

necessary. For most mental disorders, the relative

investment indifferent research approaches represents a judgment call, for which there are varying

views. In one publication, genetic epidemiologists summarized the options for schizophrenia

research in the following way (30):

The best analogy might be that of a stock

portfolio. Family, twin, and adoption studies are

low-risk, slow-growth, dependable investments

that will continue, at a modest speed, to provide

increasing knowledge about the genetics of

schizophrenia. Linkage studies are hot, new

high-risk investments that might produce great

break-throughs but also might stall or even go

bust. Individual investors will hold different

views as to the optimal balance of these alternative strategies, depending on their objective assessment of the relative chances of success or

failure and the rewards associated with each

strategy, as well as on their personal comfort

level in dealing with varying levels of uncertainty. Most investment counselors would suggest

that a portfolio should include at least some of

both kinds of investments. As a field, we would

do well to follow such advice.

Many participants at the OTA-NIMH workshop conveyed the sense that while the search for

mental disorder genes has been turbulent to date,

continued application of linkage analysis—with

an eye toward strengthened methodologies-offers considerable promise because major genes

may contribute to the disorders. One workshop

participant supported continued linkage analysis

for at least three reasons: 1 ) advances in molecular

genetics permit the comprehensive search for

[I]t is critical that we avoid premature disillusionment with linkage studies of schizophrenia.

The human brain is very complex and quite difficult to access, and schizophrenia is a common

and crippling condition. For a complex disorder

such as schizophrenia, this approach would

most likely begin with gene mapping by linkage

analysis. The aggregate results from twin and

adoption studies allow us to conclude with some

confidence that genes that influence liability to

schizophrenia exist somewhere in the human

genome. The crucial questions to which we do

not have answers are ( 1 ) How many such genes

are there? (2) How common are they? and (3)

How large are their individual effects? If there

are any relatively common genes of moderate to

large effect, we have a very good probability of

detecting them reliably in most study populations if we persevere in our study of large samples and maximize our statistical power to

detect linkage under complex modes of inheritance. If there are very many genes, none of

which has any more than a small effect on 1 iability, current methods and projected sample sizes

are almost certainly inadequate and will yield

negative or unreplicated results. . . To carry out

a truly credible execution of the linkage strategy

for a disease as complex and heterogeneous as

schizophrenia, large numbers of carefully diagnosed families and highly informative markers

are required. These resources are just now beginning to be brought into action. While definitely not offering a guaranteed success, this

approach, if allowed sufficient time to mature,

could yield truly unprecedented insights into the

etiology of this disorder.

While some enthusiastically endorse linkage

analysis of major mental disorders, and most do

not rule it out as a reasonable approach, no one disagrees that further attention is needed to better

characterize the inherited trait and familial risk
24 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

presented by these conditions by using family and

twin studies. Furthermore, other methods for finding culprit genes, the sib pair method and association studies, offer important alternatives for the

study of mental disorders.

CHAPTER 2 REFERENCES

1. Andrews, G., Stewart, G., Allen, R., et al.,

“The Genetics of Six Neurotic Disorders: A

Twin Study,” Journal of Affective Disorders

19:23-29, 1990.

2. Angst, J., Vollrath, M., Merikangas, K., et al.,

“Comorbidity of Anxiety and Depression in

the Zurich Cohort Study of Young Adults,”

Comorbidity of Mood and Anxiety Disorders,

J.D. Maser and C.R. Cloninger (eds.) (Washington, DC: American Psychiatric Press Inc.,

1990).

3. Barr, C. L., Kennedy, J.L., Pakstis, A.J., et al.,

“Linkage Study of a Susceptibility Locus for

Schizophrenia in the Pseudoautosomal Region,” Schizophrenia Bulletin 20:277-286,

1994.

4. Bassett, A. S., Jones, B. D., McGillivray,

B. C., et al., “Partial Trisomy Chromosome 5

Cosegregating With Schizophrenia,” Lancet

1:799-801, 1988.

5. Berrettini, W. H., Ferraro, T. N., Goldin, L.R.,

et al., “Chromosome 18 DNA Markers and

Manic-Depressive Illness: Evidence for a

Susceptibility Gene,” Proceedings of the National Academy of Sciences, U.S.A. 91:5918-

5921, 1994.

6. Carey, G., and Gottesman, 1.1., “Twin and

Family Studies of Anxiety, Phobic and Obsessive Disorders,” Anxiety: New Research

and Changing Concepts, D.F. Klein and J.

Rabkin (eds.) (New York, NY: Raven Press,

1981).

7. Clark, R. F., and Goate, A.M., “MolecularGenetics of Alzheimer’s Disease,” Archives of

Neurology 50: 1164-1172, 1993.

8. Clifford, C., Murray, R. M., and Fulker, D. W.,

“Genetic and Environmental Influences on

Obsessional Traits and Symptoms,” Psychological Medicine 14: 791-800, 1984.

9. Collinge, J., DeLisi, L. E., Boccio, A., et al.,

“Evidence for a Pseudo-Autosomal Locus for

Schizophrenia Using the Method of Affected

Sibling Pairs,” British Journal of Psychiatry

158:624-629, 1991.

10. Coon, H., Holik, J., Hoff, M., et al., “Analysis

of Chromosome 22 Markers in 9 Schizophrenia Pedigrees,” American Journal of Medical

Genetics, Neuropsychiatric Genetics 54:72-

79, 1994.

11. Cox, D. R., remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

12. Crow, T.J., DeLisi, L. E., and Johnstone, E.C.,

“Concordance by Sex in Sibling Pairs With

Schizophrenia Is Paternally Inherited: Evidence for a Pseudoautosomal Locus,” British

Journal of Psychiatry 155:92-97, 1989.

13. Crow, T.J., Poulter, M., Lofthouse, R., et al.,

“Male Siblings With Schizophrenia Share

Alleles at the Androgen Receptor Above

Chance Expectation,” American Journal of

Genetics, Neuropsychiatric Genetics 48: 159-

160, 1994.

14. Crowe, R. R., Noyes, R.J., Pauls, D.L., et al.,

“A Family Study of Panic Disorder, ’’Archives

of General Psychiatry 40: 1065-1069, 1983.

15. DeLisi, L. E., Bass, N., Boccio, A., et al.,

“Age of Onset in Familial Schizophrenia,”

Archives of General Psychiatry 51:334-335,

1994.

16. DeLisi, L.E., Devoto, M., Lofthouse, R., et

al., “Search for Linkage to Schizophrenia on

the X and Y Chromosomes,” American Journal of Medical Genetics, Neuropsychiatric

Genetics 54: 113-121, 1994.

17. Detera-Wadleigh, S. D., Berrettini, W. H.,

Goldin, L. R., et al., “Close Linkage of

“
Chapter 2 Research Results 125

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

C-Harvey -ras-l and the Insulin Gene to Affective Disorder Is Ruled Out in Three North

American Pedigrees,” Nature 325:806-808,

1987.

Egeland, J., Gerhard, D. S., Pauls, D.L., et al.,

“Bipolar Affective Disorders Linked to DNA

Markers on Chromosome 1 l,” Nature 325:

783-786, 1987.

Gershon, E. S., “Genetics,” in Manic-Depressive Illness, F.R. Goodwin and K.R. Jamison

(New York, NY: Oxford University Press,

1990).

Gottesman, 1.1., Schizophrenia Genesis: The

Origins of Madness (New York, NY: W.H.

Freeman, 1991).

Gottesman, 1.1., “Origins of Schizophrenia:

Past as Prologue,” Nature, Nurture and

Psychology, R. Plomin and G.E. McClearn

(eds.) (Washington, DC: American Psychological Association, 1993).

Gottesman, 1.1., “Schizophrenia Epigenesis:

Past, Present, and Future,” Acta Psychiatric

Scandinavia, in press.

Gottesman, 1.1., and Bertelsen, A., “Confirming Unexpressed Genotypes for Schizophrenia. Risks in the Offspring of Fischer’s

Danish Identical and Fraternal Discordant

Twins,” Archives of General Psychiatry

46:867-872, 1989.

Green, R. C., and Pitman, R. K., “Tourette

Syndrome and Obsessive Compulsive Disorder,” Obsessive Compulsive Disorders:

Theory and Management, M.A. Jenike, L.

Baer, and W.E. Minicheillo (eds.) (Littleton,

MA: PSG Publishing, 1986).

Gusella, J.F., Wexler, N. S., Conneally, P. M.,

et al., “A Polymorphic Marker Genetically

Linked to Huntington’s Disease,” Nature

306:234-238, 1983.

Harris, E. L., Noyes, R., Crowe, R.R., et al.,

“Family Study of Agoraphobia,” Archives of

General Psychiatry 40: 1061-1064, 1983.

Hodgkinson, S., Shemington, R., and Gurling, H., “Molecular Genetic Evidence for

Heterogeneity in Manic Depression,” Nature

325:805-806, 1987.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

Hopper, J. L., Judd, F. K., Derrick, P. L., et al.,

“A Family Study of Panic Disorder,” Genetic

Epidemiology 4:33-41, 1987.

Kelsoe, J. R., Ginns, E. I., Egeland, J. A., et al.,

“Reevaluation of the Linkage Relationship

Between Chromosome 1 1p Loci and the Gene

for Bipolar Affective Disorder in the Old Order Amish,” Nature 342:238-243, 1989.

Kendler, K. S., and Diehl, S. R., “The Genetics

of Schizophrenia: A Current, Genetic-Epidemiologic Perspective,” Schizophrenia Bulletin 19:261-285, 1993.

Kendler, K. S., Gruenberg, A. M., and Kinney,

D. K., “Independent Diagnoses of Adoptees

and Relatives as Defined by DSM-111 in the

Provincial and National Samples of the Danish Adoption Study of Schizophrenia,” Archives of General Psychiatry 51:456-468,

1994.

Kendler, K. S., Heath, A.C., Neale, M. C., et

al., “Alcoholism and Major Depression in

Women: A Twin Study of the Causes of Comorbidity,” Archives of General Psychiatry

50:690-698, 1993.

Kendler, K. S., Neale, M. C., Kessler, R. C., et

al., “Major Depression and Generalized Anxiety Disorder: Same Genes, (Partly) Different

Environments?” Archives of General Psychiatry 49:716-722, 1992.

Kendler, K. S., Neale, M. C., Kessler, R. C., et

al., “Panic Disorder in Women: A PopulationBased Twin Study,” Psychological Medicine

23:397-406, 1993.

Kendler, K. S., Pedersen, N., Johnson, L., et

al., ” A Pilot Swedish Twin Study of Affective

Illness, Including Hospital- and PopulationAscertained Subsamples,” Archives of General Psychiatry 50:699-706, 1993.

Kennedy, J. L., Giuffra, L. A., Moises, H. W.,

et al., “Evidence Against Linkage of Schizophrenia to Markers on Chromosome 5 in

Northern Swedish Pedigree,” Nature 336:

167-170, 1988.

Kety, S. S., Wender, P. H., Jacobsen, B., et al.,

“Mental Illness in the Biological and Adoptive Relatives of Schizophrenic Adoptees,”
26 I

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Archives of General Psychiatry 51:442-455,

1994.

Klerman, G. L., Herschfeld, R. M.A.,

Weissman, M. M., et al., Panic, Anxiety

Treatment (Washington, DC: American Psychiatric Press, 1992).

Maier, W., Lichtermann, D., Meyer, A., et al.,

“A Controlled Family Study in Panic Disorder,” Journal of Psychiatric Research (Suppl.

1)27:79-87, 1993.

McGuffin, P., Owen, M.J., O’Donovan,

M. C., et al., Seminars in Psychiatric Genetics

(London, England: Gaskell, 1994).

McGuffln, P., and Sargeant, M.P., “Genetic

Markers and Affective Disorder,” The New

Genetics of Mental Illness, P. McGuffln and

R. Murray (eds.) (Oxford, England: Butterworth-Heinemann, 1991).

Mendlewicz, J., Papdimitrisu, G., and Wilmatte, J., “Family Study of Panic Disorder:

Comparison With Generalized Anxiety Disorder, Major Depression, and Normal Subjects,” Psychiatric Genetics, in press.

Moran, C., and Andrews, G., ” A Familial Occurrence of Agoraphobia,” British Journal of

Psychiatry 146:262-267, 1985.

Noyes, R., Jr., “The Natural History of Anxiety Disorders,” Handbook of Anxiety, Volume

1, M. Roth, G.D. Burrows, and R. Noyes

(eds.) (Amsterdam, The Netherlands: Elsevier Science Publishers, 1988).

Noyes, R., Clarkson, C., Crowe, R.R., et al.,

“A Family Study of Generalized Anxiety Disorder,” American Journal of Psychiatry

144: 1019-1024, 1987.

Noyes, R., Jr., Crowe, R.R., Harris, E.L., et

al., “Relationship Between Panic Disorder

and Agoraphobia,” Archives of General Psychiatry 43:227-232, 1986.

Parfitt, E., Asherson, P., Sargeant, M., et al.,

“A Linkage Study of the Pseudoautosomal

Region in Schizophrenia (Abstract),” Psychiatric Genetics 2:92-93, 1991.

Pauls, D. L., Towbin, K. E., Leckman, J.F., et

al., “Gilles de la Tourette Syndrome and Obsessive Compulsive Disorder: Evidence Supporting an Etiological Relationship,”

49.

50.

51.

52.

53.

54.

55.

56.

57.

Archives of General Psychiatry 43:1180-

1182, 1986.

Polymeropoulos, M. H., Coon, H., Byerley,

W., et al., “Search for a Schizophrenia Susceptibility Locus on Human Chromosome

22,” American Journal of Medical Genetics,

Neuropsychiatric Genetics 54:93-99, 1994.

Pulver, A.E., Karayiorgou, M., Lasseter,

V.K., et al., “Follow-up of a Report of a Potential Linkage for Schizophrenia on Chromosome 22q12-q13.1: Part 2,” American

Journal of Medical Genetics, Neuropsychiatric Genetics 54:44-50, 1994.

Pulver A. E., Karayiorgou, M., Wolyneic, P.,

et al., “Sequential Strategy to Identify a Susceptibility Gene for Schizophrenia on

Chromosome 22q12-q13.l Part 1,’’ American

Journal of Medical Genetics, Neuropsychiatric Genetics, 54:36-43, 1994.

Rasmussen, S.A., “Genetic Studies of Obsessive-Compulsive Disorder,” Annals of Clinical Psychiatry 5:241-248, 1993.

Rasmussen, S.A., and Tsuang, M.T., “Clinical Characteristics and Family History in

DSM-111 Obsessive-Compulsive Disorder,”

American Journal of Psychiatry 143:317-

322, 1986.

Risch, N., “Genetic Linkage and Complex

Diseases, With Special Reference to Psychiatric Disorders,” Genetic Epidemiology

7:3-16, 1990.

Risch, N., Yale University, New Haven, CT,

remarks at “Understanding the Role of Genetic Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Office of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

Sherrington, R., Brynjolfsson, J., Petursson,

H., et al., “Localization of a Susceptibility Locus for Schizophrenia on Chromosome 5,”

Nature 336: 164-169, 1988.

St. Clair, D., “Genetics of Alzheimer’s Disease: Some Molecular Understanding of a

Diverse Phenotype,” British Journal of Psychiatry 164: 153-156, 1994.
Chapter 2 Research Results 127

58. Tienari, P., “Interaction Between Genetic

Vulnerability and Family Environment: The

Finnish Adoptive Family Study of Schizophrenia,” Acta Psychiatric Scandinavia

84:460-465, 1991.

59. Torgersen, S., “Genetic Aspects of Anxiety

Disorders,” Archives of General Psychiatry

40: 1085-1089, 1983.

60. Torgersen, S., “A Twin-Study Perspective of

the Comorbidity of Anxiety and Depression,”

Comorbidity of Mood and Anxiety Disorders,

J.D. Maser and C.R. Cloninger (eds.) (Washington, DC: American Psychiatric Press Inc.,

1990).

61. Torrey, E. F., “Are We Overestimating the Genetic Contribution to Schizophrenia?”

Schizophrenia Bulletin 18: 159-170, 1992.

62. Tsuang, M. T., “Genetics, Epidemiology, and

the Search for Causes of Schizophrenia,”

American Journal of Psychiatry 151:3-6,

1994.

63. Tsuang, M.T., and Faraone, S. V., The Genetics of Mood Disorders (Baltimore, MD: The

Johns Hopkins University Press, 1990).

64. U.S. Congress, Office of Technology Assessment, The Biology of Mental Disorders, OTABA-538 (Washington, DC: U.S. Government

Printing Office, September 1992).

65. Weissman, M. M., “The Affective Disorders:

Bipolar Disorder and Major Depression,”

Concepts of Mental Disorder, McClelland

and Kerr (eds.) (London, England: Gaskell,

1991).

66. Weissman, M. M., “Family Genetic Studies of

Panic Disorder,” Journal of Psychiatric Research, (Suppl.) 27:69-78$ 1993.

67. Weissman, M. M., Gershon, E. S., Kidd, K. K.,

et al., “Psychiatric Disorders in the Relatives

of Probands With Affective Disorders: The

Yale University National Institute of Mental

Health Collaborative Study,” Archives of

General Psychiatry 41: 13-21, 1984.

68. Weissman, M. M., Merikangas, K. R., Wickramaratne, P., et al., “Family-Genetic Studies of

Psychiatric Disorders,” Archives of General

Psychiatry 43: 1104-1116, 1986.

69. Weissman, M. M., Wickramaratne, P.,

Adams, P. B., et al., “The Relationship Between Panic Disorder and Major Depression:

A New Family Study,” Archives of General

Psychiatry 50:767-780, 1993.

70. Woodman, C. L., “The Genetics of Panic Disorder and Generalized Anxiety Disorder, ’’Annals of Clinical Psychiatry 5:231-240, 1993.
R

esearch involves people. People participate in research.

People may benefit from research-driven improvements

in clinical practice. And people face social perceptions

and policies that stem from research.

Study of the genetic factors involved in mental disorders is no

different. However, the polemics and controversy surrounding

the genetics of mental disorders forestall reasoned discussion of

what this research means to people with mental disorders and

their families. The complexity of this research further compounds

consideration of its clinical and social implications. And the uncertainty of the genetic mechanisms involved in mental disorders

deters many from spending time (or money) on this topic.

It maybe unwise to devote a great deal of time and resources to

the consideration of specific policies and implications of the genetics of mental disorders, given the early stage of research findings. But no discussion also seems an unwise choice. Clinicians,

policy makers, people with mental disorders and their family

members are left to decipher the complicated, confusing, and unevenly reported research results. No discussion also means that

little opportunity for interdisciplinary dialogue exists among geneticists, mental health professionals, genetic counselors, ethicists, social analysts, and primary and secondary consumers.1

People have no formal venue for voicing their concerns; experts

outside of the mental health field have no official forum in which

to share their experiences and knowledge.

1 Primary consumers are individuals with mental disorders; secondary consumers are

family members or others who help care for people with these conditions.

for

Society 3

129
30 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Publicized abuses over the course of the 20th century remind us of the need to safeguard the rights

and well-being of human subjects involved in research. In general, the withering eye of publicity served to

vanquish studies where abuse occurred and often led to policy reform. A clarion call was sounded in the

Nuremberg trials of Nazi physicians, who used prisoners of concentration camps as subjects of “biomedical experiments” during World War Il. During the trials, the accused defended their actions by arguing that

it was not common professional practice among physician-investigators to seek consent of research subjects. In response to this defense, in 1948 the judges crafted the Nuremberg Code, which sets forth 10

“basic principles to satisfy moral, ethical and legal concepts” in the conduct of human-subject research.

Scientific research involving human subjects became common in the United States shortly before the

outbreak of World War Il. By the 1960s, however, concerns about unethical research practices began to

surface. A case in point was the intentional infection with hepatitis of residents of the Willowbrook State

School for the Retarded, In a series of experiments, begun in 1956 and spanning over a decade, institutionalized children with mental disabilities were infected with live hepatitis virus in an effort to develop a

vaccine. The scientists justified their procedures by noting that hepatitis ran rampant through the institution

and that all of the children would eventually contract the disease. Further, they maintained that only children whose parents had given their written consent were included in the experiments. Critics challenged

these arguments, suggesting that parents may have been coerced into volunteering their children as a

means of procuring placement at Willowbrook. Moreover, parents were misled to believe their children were

to receive a vaccine against the virus and they were not informed of the risk to their children of developing

chronic hepatitis and the possible link to cirrhosis in later life. Criticism eventually brought the experiments

to an end in the mid-1960s.

Perhaps the most notorious case of unethical research in the United States is the Tuskegee Syphilis

Study. From 1932 to 1972, scientists conducting a U.S. Public Health Service study of 400 African American men suffering from syphilis deliberately withheld treatment from them in order to study the effects of

allowing the disease to take its course. The men were told only that they were receiving free treatment for

The workshop hosted by the Office of Technology Assessment (OTA) and the National Institute

of Mental Health (NIMH) in January 1993 provided one of the first opportunities for comprehensive discourse of the issues raised specifically

by genetic studies of mental disorders. Experts

within and outside of the mental health field, as

well as consumer representatives, discussed ethical issues that emerge during this research, the

clinical implications of what we know about the

genetics of mental disorders, and how society

views these topics. The panel’s deliberations

evinced the concerns many have about the genetics of mental disorders and characterized issues

that have already emerged. This chapter documents the workshop discussion under three

headings:

. ethics and research,

■ genetic counseling, and

● public perceptions and social implications.

ETHICS AND RESEARCH

Diagnostic and treatment advances result from research, including studies involving human subjects. While few question the value of biomedical

research in general, publicized abuses over the

course of the 20th century highlight the need to

safeguard the rights and well-being of research

participants (box 3-1 ). Research of the genetic factors involved in mental disorders is no different;

protection of research participants is a preeminent

concern. However, the necessary involvement of

whole families, the stigma and discrimination at-
Chapter 3 implications for Society 131

tached to genetic and mental disorders, and the po- from research involving human subjects. Justice

tential impact of mental disorders on reasoning

and judgment compound and complicate ethical

concerns. Workshop participants elaborated some

of the difficult ethical issues that emerge from this

research. In addition, several participants signaled

the need for guidance on how to better deal with

these situations.

The ethical conduct of research involving human subjects rests upon a bedrock of three values,

first enumerated by the National Commission for

the Protection of Human Subjects of Biomedical

and Behavioral Research (National Commission):

respect for persons, beneficence, and justice

(46,65,68). Respect allows people to make and

pursue their own decisions in an informed and

voluntary manner. Beneficence seeks both to protect individuals from harm and to ensure benefits

refers to the fair and uncoerced selection of human

subjects for research, especially among vulnerable populations.

The regulatory translation of these ethical principles guides nearly all research with human subjects today. Specifically, federal regulations

demand that all federally funded human research

projects must be reviewed and approved by an

Institutional Review Board, or IRB (45 CFR

46.103(b)). This multidisciplinary panel considers risks, benefits, subject selection, and consent

issues for proposed studies involving human subjects. Federal regulations further require that informed consent be obtained from each subject,

although this can be waived in certain circumstances. In order to provide informed consent, the

anticipated benefits and potential risks associated
32 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

with an experimental procedure must be explained to the individual; he or she must understand these factors, rationally weigh them, and

then make a voluntary decision as to whether or

not to participate.

Informed consent, while straightforward in

principle, can be challenging to obtain, especially

in complicated research designs. Packed with

technical information, lengthy, or even incomplete, consent forms may baffle all but those with

specialized expertise. One workshop panelist described this concern and the need for one-on-one,

ongoing discussion to achieve informed consent (8):

We now have a pretty impressive informed

consent form for breast cancer genetic research

after a lot of work. . . on two single typed pages.

Academically, we may have finally thought

through many issues and anticipated some of

them. But how do potential participants process

all this and make a decision for themselves that

they want to or do not want to participate in this

research?. . . Our most successful endeavors

have been engaging individuals in one-on-one

conversations. . . True informed consent is a

discussion and a long, ongoing process.

Although never translated into regulation, the

National Commission acknowledged that mental

disorders, which impact on cognitive processes,

emotions, and behavior, may sometimes impair

the ability to provide informed consent (65). The

limited research data that exist fortify this observation. Severe symptoms of schizophrenia, including psychosis, paranoia, or delusions, can

compromise an individual’s competence to provide informed consent (3,32).

Of course, if a person is found incompetent to

provide informed consent, proxy consent, given

by a legally authorized representative, may be required and under certain circumstances requirements for informed consent may be waived (56).

However, these approaches to consent are unlikely to be used commonly. For one, even hospitalized individuals with schizophrenia exhibit a

considerable range of capacities to provide informed consent (32). And as one panelist noted,

IRBs around the country may not be informed on

this subject (57):

A meeting held recently, jointly sponsored by

the Office for Protection from Research Risks,

the National Center for Human Genome Research, and NIMH . . . found that institutionwide IRBs know relatively little about mental

disorders and they may need to be better informed about consent issues, substituted judgment issues and the like.

Perhaps most importantly, people with mental

disorders and their families urge greater participation in research (24):

I’m not at all certain that we have done all

that we can or the best job we could in terms of

really thinking appropriately about informed

consent. I appreciate the difficulties and understand the concerns that people have about the

impact on the research enterprise, but I also

think that we have to respect what others are telling us about the increasing role that consumers

are playing in their own lives and in shaping

their own lives. My own information that we

gather from talking to people in our office is that

the work that’s done is focused on getting a signature. Get the signature, get the paper signed.

Sometimes there’s a good description and discussion of what’s going on and what may occur

and what the research is pointing towards and

sometimes it’s not so good and not so thorough.

In almost all cases it occurs once. I think we

need to realize particularly in research of this

type that we may want to see it as less an event

and more a process. We may want to be sure as

the research unfolds that those people most directly involved and affected continue to be updated and advised and understand what, in fact,

is going on.

So I think we need to think more comprehensively about a partnership with the people who

are involved as research subjects and recognize

there’s a lot more to consent than getting someone who is now not under the protection of some

of the rest of the field because they are specifically excluded. . . There is some unfinished

business in that regard. I think we need to be par-
ticularly sensitive to respecting our duty to inform and perhaps inform more than one way

more than one time so that people can be full

participants and partners in the research.

The conclusions of the workshop discussants—that informed consent requires more than a

onetime paper signing event, that the issue of

mental disorders and informed consent must be

taken seriously, and that IRBs require support and

education---echo the findings of a recent report

from the Office for the Protection from Research

Risks (OPRR)2 (25,69). Panelists also urged

greater sensitivity to the families of participants in

research (34):

In mental illness the research subjects maybe

fairly young . . . between the age of 18 and

21. . with serious mental illness, and the families may be very involved in the individual’s

life. . . I would maintain in that type of situation

. . . that the . . . ethical obligation (for informed

consent and ongoing communication) extends

to the family as well.

Let me give you an example. Say a family has

identified a particular research protocol at a particular university and has informed the individual who has the mental illness of that program and

they’ve made a collective decision that that program is an appropriate one and the individual

goes to the program and at some point sits down

and is informed about the research protocol and

the risks of the research and the potential benefits of the research, et cetera.

In that type of situation where there is no apparent disagreement between the individual and

his or her family, it would be my contention and I

believe it’s NAMI’s [National Alliance for the

Mentally Ill] contention that the obligation on

the part of the researchers to inform would extend to the family. In other words, they would

have an obligation to sit down with the family as

well as that individual.

I realize that I just introduced a new subject,

but that’s something that we hear about a great

Chapter 3

deal, that families

implications for Society I

initiate a referral and then

33

they’re completely written out of the process.

Several panelists expressed the opinion that

family members should be more involved in research, participating in the consent process, in ongoing contact with researchers, and as members of

IRBs (5,18). In pedigree studies, families are necessary participants, which challenges the traditional vantage point of bioethics. Concern for the

individual subject has directed the evolution of

bioethical concepts of informed consent, confidentiality, and voluntary participation. Researchers and ethicists on our panel noted the difficulties

of adapting these ethical principles to studies involving whole families. One such issue raised by

genetic research and discussed at the workshop is

disputed paternity (14):

I feel privacy must be breached . . . in situations involving disputed paternity. I’ve had two

cases where two daughters of two different individuals thought they were at risk for Huntington’s when in fact they were not. That brings up

two points. Obviously, they were told, in fact, in

one case I had to tell the individual because the

mother would not. In the other, the mother did

eventually, after a lot of arm twisting, tell the

daughter that, in fact, she was not at risk. In both

cases, these two young women were pregnant.

Now, that creates another issue and you might

argue that the mother’s privacy shouldn’t be

breached, but I feel that there’s a right—that the

daughter has a right to know something that impacts on the rest of her life, just as well as her

mother has a right not to have anyone know what

she did some 20 years earlier.

As the above example illustrates, pedigree research can reveal previously unshared information about biological relationships among family

members. Such information pits the rights of

some family members to their privacy against the

rights of others to know if they or their children are

at increased risk for a condition. Although researchers worry about discomforting and discour2 This office is located in the National Institutes of Health, U.S. Department of Health and Human Services.
34 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

aging would-be research participants, several

panelists gave voice to the opinion that pedigree

research’s ability to expose disputed paternity is

required for true informed consent (18,46):

In discussing the business about informed

consent, it’s clear that unless that potential is

brought out, one could be accused of violating

the ethical principle of informed consent. In other words, if that’s a possibility-even a relatively low risk-it must be revealed. And its not

relatively low, it’s relatively high. In some communities that I deal with, it’s not five percent,

it’s more like 15 or 20 percent. . . There are two

ways of dealing with it. One is to have this in the

informed consent form, and the other is to take

the pedigree by asking, “Is this man the father of

all your children?” (46).

Disputed paternity is not the only aspect of pedigree research that may incur conflict among family members. The very issue of informed consent

becomes more complex, as described by one

workshop participant (15):

One of the things that is unique about pedigree studies is the fact that it’s no longer a dyadic

relationship between a patient and a person involved in a clinical trial or other research. There

are other people involved in the family. Does every person on that pedigree have to have an informed consent statement before you publish it?

Do you publish it? How much clinical information do you include? Should you alter the pedigree to prevent identification? All these

questions about how to handle the information

in pedigree research are being raised without

much inspection except by the ethical norms of

the people doing it.

Not only does a single individual consent to

participate in a pedigree study, but the participant

must be informed that relatives will be asked to

participate (56,69). Family members participating in the study must be given the option to consent as well. Researchers must decide and inform

participants of which information will be shared

with family participants. A medical geneticist and

ethicist on the workshop panel noted (46):

Most IRBs I am familiar with . . . treat the

pedigree as part of the patient record and therefore all the information related to that patient is

considered confidential in the same way that

clinical records are considered confidential.

They don’t approach any other members of the

family for testing unless they get the permission

from the proband or consultant in the pedigree.

Of course, problems can emerge if family

members disagree about participation in a research project. An example from research in Huntington’s disease is illustrative (14):

A young woman completed a Family History

Questionnaire and signed an informed consent

form placing her family on the Roster. When

asked to identify family members who would be

best suited to complete an affected questionnaire, she identified her brother. A packet of information concerning Huntington’s disease and

explaining the purpose of the Affected Questionnaire was sent to the brother. Several days

after the questionnaire was mailed, a certified

letter from the brother’s attorney was received

stating that he wanted “his family” removed

from the Roster.

Family members may have different feelings

about a disease or about participating in research.

Individuals may want to ignore the presence of a

disease within their family, deny its existence, or

may guard such information as a secret, even from

other family members. Stigmatized genetic

conditions and mental disorders are certainly sensitive issues for many families. These concerns

highlight the unique kinds of risks that pedigree

studies pose to individuals and families. While

physical risks, such as possible side effects of a

new medication, may be minimal or nonexistent

in pedigree research, information about genetic

status or mental disorder pose what a recent

OPRR report calls psychosocial risks. “Information can provoke anxiety and confusion, damage

familial relationships, and compromise a subject’s insurability and employment opportunities”

(69). IRBs may not appreciate the nature of these

risks and thus may dismiss them as insignificant, a

neglect that OPRR cautions against.

Because of the psychosocial risks presented by

genetic research, confidentiality of information

becomes paramount. Experts advise that as much
information as possible be kept private from other

family members participating in genetic studies.

Information that must be revealed should be disclosed only with the full knowledge and agreement of each participant. But privacy o r

confidentiality concerns extend beyond family

members. Family and genetic studies of mental

disorders can unearth a host of sensitive information, such as the presence of a mental disorder, increased family risk for a condition, other

behavioral problems, substance abuse, and criminal history. This type of information in the hands

of private insurers, employers, or others could

pose grave risks to an individual participating in

research. To address this concern, NIMH encourages the use of certificates of confidentiality to

prevent access to individually identifiable research data by insurance companies, government

authorities, or other third parties. Evolved in the

context of substance abuse research, this certificate protects investigators from the compulsory

revelation of potentially harmful research data (42

CFR Part 2a, 1991). Indeed, an NIMH scientist indicated that the mental health research community

increasingly uses certificates of confidentiality

(57).

The certificate of confidentiality does not preclude reporting cases of child abuse or imminent

suicidal or homicidal behavior. Neither does the

certificate of confidentiality inoculate against the

inadvertent revelation of information by the research subject, as noted at the meeting (57):

Let me warn you that there’s a potential leak

in the system. Not so much in the system, but in

the way in which it’s used practically. Individuals who go for testing before they enter a research protocol may be told, “Well, we’ll be

happy to enter you in our protocol, but we need

to be sure about the diagnosis. We need to have

certain blood tests,” and the person goes in to

their private physician and says, “I want to get a

blood test to check out X, Y, and Z, and the reason is that I’m about to participate in a research

study on the genetics of Alzheimer’s disease.”

So, the physician writes down, “To participate in

research study on Alzheimer’s disease, ordering

the following studies,” and files for insurance

Chapter 3 Implications for Society I 35

reimbursement. The person himself has already

let out of the bag information which can and will

go to the insurance company.

Apprising research participants about this potential problem is yet another important component of informed consent. Finally, a representative

(12) from one consumer organization—the National Depressive and Manic-Depressive Association—notes that:

[a] Confidentiality Statement serves no purpose if the storage of research data is accessible.

Any data storage device that has telecommunication ability, or that is networked to such a

main server is vulnerable. ALL RESEARCH

DATA WITH ANY FORM OF PATIENT IDENTIFIER, INCLUDING “INTERNAL CODE,”

MUST BE ISOLATED DURING WORK AND

KEPT IN A STAND-ALONE DATA BASE

WITH NO TELECOMMUNICATION INTERFACE AT ALL [capitalization in original letter].

We feel this is absolutely necessary, absolutely

imperative to protect information from incursion by 1 ) government at any level, 2) insurance

companies, 3) current or prospective employers,

4) media snoops, 5) current or prospective families, and 6) hackers. Should the research data for

any particular individual be requested, that patient should be asked to execute a specific Release of Information.

While not discussed in great detail, workshop

participants also raised concerns about how to

handle data and biological materials after a research subject withdraws from a study or in future

studies, for which informed consent was not specifically garnered. Federal regulations clearly require that subjects be free to withdraw from a

research project without penalty or loss of benefits

to which they are otherwise entitled. Regulations

do not address the use of data or tissue samples

should a participant decline further study participation. A panelist noted that the ruling in a 1990

California Supreme Court case—John Moore v.

The Regents of the University of California—provides guidance (57). In that case, the court held

that cell lines transformed from a donated blood

sample are not the property of the person who donated the sample. In line with this ruling, work-
36 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

shop participants speculated that people who

withdraw from a genetic research project might

not necessarily be able to require destruction of all

of the information and biological materials previously provided. There are questions about this

case’s applicability, however. For example, could

a withdrawing research subject request that all

identifiers linking the data or samples to him or

her be purged? Also, Moore constitutes binding

legal authority only in California. As of this writing, it has not been adopted in other jurisdictions.

Having invested considerable time and resources into the collection of data and biological

materials from extended families, researchers

may desire to test new genetic markers or hypotheses as they arise. Must researchers seek renewed

informed consent? Most experts do not advise the

destruction of valuable and perhaps irreplaceable

resources. On the other hand, relevant ethical concerns raised by a new study may make renewed informed consent indispensable. A Huntington’s

disease researcher described his approach to this

problem (14):

I would be concerned if I collected DNA on

people and then simply discarded it when it

might be very useful to them. So I would suggest

that you have an informed consent saying that

we ‘re going to keep this DNA and it will on] y be

used with your written consent, like we do in our

Huntington’s disease DNA bank.

OPRR offers similar guidance (69):

Where a new study proposes to use samples

collected for a previously conducted study, IRBs

should consider whether the consent given for

the earlier study also applies to the new study.

Where the purposes of the new study diverge

significantly from the purposes of the original

protocol, and where the new study depends on

the familial identifiability of the samples, new

consent should be obtained.

What if research results become clinically relevant? Should someone be informed if it becomes

clear that he or she has a 90 percent risk of developing a serious medical disorder, for which preventive interventions or effective therapies exist?

Several obstacles preclude a simple yes in response to this question. An individual who participates in research may not want to know such

information. A researcher in a laboratory, who has

had no contact with the subject, may make the

health risk discovery. In this situation, who contacts the research subject? Researchers assert that

the question should be put to subjects directly: if

we discover that you are at risk for a severe disease

which is preventable, do you want us to inform

you? NIMH’s approach to this topic offers one example. It advises its grantees that consent documents clearly indicate whether subjects will be

given the results of genetic tests used in research

(56).

GENETIC COUNSELING

The standing room only crowds at seminars

hosted by NAMI hint at the desire—among family

members and people with mental disorders—for

more information about the genetics of mental

disorders (24). “[W]hat invariably happens is that

people line up from the audience and they say,

“Let me tell you about my history. I have this, this,

and that. What’s the risk [to me and my family]?”

(28). While genetic counseling for mental disorders apparently occurs rarely (29,63)—an informal survey of genetic counselors in the New York

area indicated that only a small number of people

request counseling on mental illness (42)-consumer representatives at the OTA-NIMH workshop testified to a hunger for knowledge about

genetics among people with mental disorders and

their families (5).

[T]here is a tremendous hunger for knowledge. Not for it to be packaged to us, but for us to

be given both the uncertainty and the certainty. . . Consumers want to know. The first thing

that almost every consumer said [in a survey of

650 consumers in Virginia] is “I want to know,

even if it’s uncertain, even if it’s complicated, I

want to know,” because mental illness for so

many people has been presented as a mystery or

as something that we are responsible for. To

have information, even well-informed guesses

given to us as that, is something we hunger for.
Chapter 3 implications for Society 137

The relay of genetic information occurs formaly in the context of genetic counseling. A recent

report from the Institute of Medicine (35) defines

genetic counseling as:

the process by which individuals and

families come to learn and understand relevant

aspects of genetics; it is also the process for obtaining assistance in clarifying options available

for their decisionmaking and coping with the

significance of personal and family genetic

knowledge in their lives.

The first question that needs to be addressed is

whether genetic counseling is appropriate for

mental disorders at all. A variety of factors would

seem to answer no. The genetic contribution to

these conditions is complex and incompletely understood. Certainly, there are no genetic tests for

mental disorders. Even what is inherited is unclear. And genes by no means account for the

whole picture. As indicated in chapter 2, mental

disorders are generally considered multifactorial

conditions; genetic and nongenetic factors are

both involved. Furthermore, there is no known

way to prevent the mental disorders considered in

this report (although treatment may prevent relapse of symptoms in some conditions).

The enumerated rationale against genetic counseling for mental disorders neglects both the

strengths and common application of genetic

counseling as well as the desire for information

among consumers. Genetic counseling is not simply about single gene disorders, disorders for

which there are genetic tests, or the certain prediction of disease; it has a much broader application.

The whole field of genetic counseling evolved

around the concept of relaying risk information,

probabilities, and uncertainties. Principles

derived from genetic counseling-concerning

risk communication and respect for client autonomy-can inform the relay of genetic information

concerning mental disorders (8). As noted in a recently published psychiatric genetics text: “[A]n

informed and responsible genetic counseling service has a small but definite current role, and this

is likely to increase in the future” (43).

It is true that no known interventions can prevent the development of the mental disorders discussed in this background paper. But, once again,

mental disorders are not unique in this regard.

Treatments effective for many people with mental

disorders are available. Awareness of increased

risk for a condition can help alert individuals to

the earliest signs of a condition, permitting early

treatment that may prevent the most debilitating

symptoms and long-term impairment. Genetic

counseling also offers an opportunity to correct

common misperceptions about disorders with a

genetic component: namely that genetic conditions are impossible to treat or that these conditions require biological treatment (43).

Many times a person with a severe mental disorder or his or her family members fear that children or siblings face a similar fate: a severely

disabling and chronic condition. Not infrequently,

severe mental disorders afflict generation after

generation in a family. In this situation, information about the genetic risk for a condition can relieve fears. As noted at the workshop by the

executive director of NAMI, and the mother of a

daughter with schizophrenia (24):

Family members attending workshops and

lectures on the genetics of mental illness almost

always bring questions “This is my family. What

do you think?” Peoples’ levels of anxiety are

enormously high and almost always their reaction is “It’s not as bad as I thought. We’re not

fated to have these dreadful illnesses in their

most dreadful form just because we want to have

a human experience and reproduce and have an

extended family.

So, there’s an enormous amount of misunderstanding and partial understanding, even among

families, and certainly families in the Alliance

are as well educated and knowledgeable about

these disorders as any. So that the provision of

knowledge offers an enormous amount of relief.

Recurrence risk is the most elementary information transmitted in genetic counseling

(7,8,35,61)—an individual’s risk of inheriting a

condition. For mental disorders, no genetic test
38 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

ObsessiveBipolar Major compulsive Panic

Schizophrenia disorder depression disorder disorder

General population 1.070 0.8% 4.9% 2.6% 1.6%

First-degree relative (parent,

child, or sibling) 9.0-1 13.0%a 4.0-9.070 5.9-1 8.4% 25.O% 15.O-24.7%

Bethesda, MD, 1992.

can lead to an individualized assessment.3 Rather,

estimates of risk reflect pooled data from family

studies, with varying levels of information available for different disorders (tables 3-1, 3-2, and

3-3). Empirical risk estimates convey the probability of mental disorder among family members.

For example, while approximately 1 percent of the

general population will develop schizophrenia,

nearly 10 percent of those with a first-degree relative with schizophrenia will become afflicted.

First-degree relatives in general face a tenfold increased risk for schizophrenia.

Individuals with mental disorders and family

members may find comfort in knowing that a

mental disorder is not inevitable for loved ones.

But recurrence risk estimates do present difficulties. The concept of empirical risk can be difficult

to understand and act upon, which is why experts

in genetic counseling emphasize the importance

of risk presentation and interpretation (4,35,64).

How an individual interprets risk estimates varies

depending on how the risk is perceived and communicated. Research into several genetic conditions shows that a variety of factors influence the

perception of recurrence risk, including the nature

of the illness and its perceived burden. While little

research has focused on the perception of risk or

perceived burden of mental disorders, existing

data suggest diverging experiences among primary and secondary consumers. In one small study,

92 percent of well family members versus 25 percent of affected individuals viewed schizophrenia

as a severe, debilitating disorder entailing extreme

burden (55). Only 29 percent of the well family

members, versus 66 percent of individuals with

schizophrenia, reported that they would have children. In another study, 19 people with bipolar disorder and their well spouses were asked about

their perception of the disorder: approximately 50

percent of well spouses compared with 5 percent

of the bipolar patients indicated that they would

not have married and would not have had children

if they had known more about bipolar disorder

(59).

Perceptions of risk and mental disorders are not

the only obstacles to genetic counseling. Simplified, recurrence risk data itself can be misleading.

Recurrence risk estimates do not distinguish the

severity of disorder or the age of onset among

family members. They provide no information

about the genetic mechanisms at play. Recurrence

risk in a particular family may greatly exceed or

fall below the tabulated estimates. For example, if

several members of a family have a particular

mental disorder, usually with an early age of onset

and severe course, other family members are more

3 Even when genetic tests are available for a disorder, predictive ability can fall short of the absolute, reflecting the specific genetic factors at

play and always present possibility of human error.
Chapter 3 implications for Society 139

Risk to sibling Risk to sibling

when neither when at least one

parent has a mood parent has a mood

Study Proband diagnosis Sibling diagnosis disorder (percent) disorder (percent)

Rudin, 1920

Schulz, 1930s

Luxenburger, 1930s

Pollock, Malzberg,

and Fuller, 1939

Stendstedt, 1952

Reich, Clayton, and

Winokur, 1969

Johnson and

Leeman, 1977

Angst et al., 1980

Mood disorder

Mood disorder

Mood disorder

Mood disorder

Mood disorder

Bipolar disorder

Bipolar disorder

Bipolar disorder

Bipolar disorder

Mood disorder

Mood disorder

Mood disorder

Mood disorder

Mood disorder

Mood disorder

Mood disorder

Bipolar disorder

Unipolar disorder

7.4%

14.3

3.4

1.3

13.5

10.0

18,4

1.2

4.1

23.8%

26.1

16,1

3.8

17,9

21.0

23.2

5.6

8,4

likely to develop the condition than average estimates of risk suggest.

Several implications flow from the limits on recurrence risk information for mental disorders.

Sensitivity to varying understanding of illness and

probability, as well as personal and cultural factors, must imbue genetic counseling. Average estimates of recurrence risk cannot stand alone; a

careful diagnosis and family history provide an

essential framework for the individualized interpretation of recurrence risk data (box 3-2). Finally,

workshop participants concurred that more data

are needed to better characterize specific risks that

family members face in order to inform genetic

counseling.

Genetic counseling extends beyond communicating recurrence risk. A complex tangle of concerns and questions impel the pursuit of

information on genetics and mental disorders.

One workshop participant, who is an expert in genetics and mental disorders, described a typical

scenario (20):

A couple, who was contemplating having a

family, sought genetic counseling on depression. The wife had experienced her first bout of

severe depression. She expressed concern that

symptoms may flair up postpartum, jeopardizing her job, the income from which was crucial

for the family. They worried aloud about their

relationship which was shaken by the depressive

episode and the husband’s ambivalence about

having a child. These are common concerns expressed in genetic counseling: people are generally confronting a new diagnosis, fear the worst,

not just in terms of risk to a child, but also in

terms of the impact of the disorder on the family

and the impact of a pregnancy and child-rearing

on the health of a parent dealing with mental

illness.

The panoply of concerns surrounding mental

disorders and genetics underscores what genetic

counselors are realizing increasingly: the relay of

genetic information occurs in a therapeutic relationship (4,8,35). Support, counseling, and followup services can assist individuals and their
40 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Percentage

Relationship of risk

General population 1%

Spouses 2

Third-degree relatives

First cousins 2

Second-degree relatives

Uncles and aunts 2

Nephews and nieces 4

Grandchildren 5

Half-siblings 6

First-degree relatives

Parents 6

Siblings 9

Children 13

Siblings with one schizophrenic parent 17

Dizygotic twins 17

MonoZygotic twins 4 8

Children of two parents with

schizophrenia 46

a Risk estimates based on pooled data from the more than 40 systematiC family and twin studies between 1920 and 1987,

SOURCE. 1.1. Gottesman, Schizophrenia Genesis: The Origins of Madness (New York, NY W.H, Freeman, 1991).

families in coping with a diagnosis of mental disorder, the risk family members face, and life decisions that may follow. Sensitivity to an

individual’s willingness and ability to receive genetic information is but the first demonstration of

this psychotherapeutic component of genetic

counseling. The provider of genetic services

needs to be sensitive to the concept of the “teachable moment,” the point at which an individual,

couple, or family is most able to comprehend and

absorb the information being given. A primary

consumer at the OTA-NIMH workshop described

the framework for the delivery of genetic information—the realization that one’s life is altered by a

mental disorder (5):

I need to know that . . . the information is

there if I need it. . . As somebody with a primary

psychiatric diagnosis, I will say that it is a process that one goes through of accepting that one

first of all has an illness of this sort. I think that

we go through stages that are almost like Kubler-Ross’ stages of accepting death because who

I believed I would be, who my family believed I

would be, is not who I am, We die to ourselves.

We die to our hopes, we die to our family’s hopes

and somehow we have to begin to find life beyond that. And we need to know that there is

some information out there and we would like to

draw from it because we also reconstruct our

lives. We reconstruct who we are in the shifting

ground of our disorder.

Providing information only upon request is an

overriding principle of genetic counseling. It signals not only a sensitivity to consumer receptivity,

but the value placed on individual autonomy in

making life choices. Respect for individual autonomy drives nondirective counseling, which does

not explicitly or implicitly make judgments on

such personal decisions as marriage and childbearing. Medical geneticists harken to the wisdom

of helping people at higher risk for a disorder to

make decisions for themselves, by detailing the

experiences and decisions that others have made

(14):

Invariably I’m asked “Should I have children

or not?” When that happens I tend to use Yogi

Berra’s edict. When you come to a fork in the

road, take it. What I mean by that is that people

confronting similar risks make different decisions and I provide them examples.

One was Marjorie Guthrie. When she was invariably asked: Why did you have children, she

would say, “Well, Woody had 45 fantastic years

of life, very productive, etc., and I had three

children. I am delighted I had them.” That one

perspective.

The other side is the case of the president of

our Huntington’s disease association; we had

her come to talk to our medical students. She

would say when asked that question: “Oh, I

would never dream of bringing children into the

world.”

I would point out both sides of these situations to this person and say “By the way, there

are a lot of people on both sides and therefore

whichever decision you’re going to make and
Chapter 3 implications for Society 141

In 1978, Tsuang enumerated several steps required in genetic counseling for mental disorders.

These guidelines were the first published information on the subject. While genetic counseling has

evolved since that time, it is useful to review this earlier set of recommendations, which makes clear the

need for accurate diagnosis, the limitations of genetic risk information, and the need to dispel any

myths that may exist.

Dispel any myths. Many people have erroneous beliefs about mental disorders and genetics. They often

equate genetic risk with the certitude of disease and believe that a genetic disorder is untreatable. At the

outset of any counseling session, it is incumbent on the care-provider to dispel such myths, clarifying the

multifactorial nature of most mental disorders and the availability of effective treatments.

Establish an accurate diagnosis. Accurate prediction of genetic risk rests on accurate diagnosis, sometimes difficult to obtain in mental disorders. Necessary resources for a diagnosis include information from

personal interview, available medical records, and relatives.

Obtain a comprehensive family history. While collecting family history data—via interview of the individual seeking genetic information, direct interview of relatives, and medical records—poses difficulties, family

history is essential for genetic counseling. It permits a more individualized risk assessment.

Estimate recurrence risk. Based on diagnostic information and family history, a counselor can estimate

the risk of mental disorder to an individual and his or her family members. In conveying the recurrence risk

that an individual faces, a counselor discusses the limits of empirical risk estimates, Including the lack of

knowledge on genetic mechanisms involved and severity of condition that may arise.

Provide a framework for decisionmaking. Individuals seeking genetic information often do so in the context of personal decisions on marriage and childbearing. What the genetic counselor can provide is an

objective and accurate portrait of the disorder, its treatment, related disability, and the financial supports

and other services available and required. While advice on family planning is inappropriate, information on

different decisions and experiences regarding genetic information may help clarify the factors involved in

such personal decisions. Simply listening to the concerns and desires of individuals seeking genetic information also may help them cope with their illness and its impact on their lives.

Follow up the counseling session. Followup of a counseling session is integral to the process. A followup

contact confirms accurate recollection of genetic information, can address any new questions that have

arisen, and in general demonstrates support and sensitivity. Finally, a written record of the information

derived in genetic counseling, for any future use, should be forwarded to the individual and/or his or her

primary mental health care provider.

SOURCE M.T. Tsuang, “Genetic Counseling for Psychiatric Patients and Their Families, ” American Journal of Psychiatry

1351465-1475, 1978

I’m certainly not going to tell you which one to planning. In this context, highly charged issues

make, there are a lot of people who would agree can emerge for people with mental disorders (24).

with you and leave it at that. When I talk to and listen to many consumers,

Many people with a mental disorder (or any they are not all nearly as supportive of this kind

condition that is genetic) and their family mem- of effort as we might like them to be. The reason

bers confront the decision of whether that individ- is because we have an unfortunate history in

ual should have a child. Indeed, information on psychiatry, in public psychiatry in particular, of

genetics is often sought in the context of family coercion, control, and sterilization in state hos-
42 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

pitals. These things, we feel, have receded into

the misty past but they’re right up close to folks

who are living with these disorders. So, when

they hear you talking about genetic counseling,

they think what you’re really saying in code is,

“I’m going to tell you how you should not have

children. If I talk to you long enough and strong

enough, you will believe me and you will do

what I am counseling you to do.”

I certainly understand that’s not what the goal

of genetic counseling is, but that’s how it’s understood and that’s how the public wants it to be

done for people with these disorders. . . The outcome that many people are seeking is exactly

the eugenic outcome that you described. . .

That’s what the whole incredibly powerful disability rights movement opposes. Mentally ill

people are now part of that movement. The disability rights movement is not at all warm toward this aspect of your work because there’s a

very strong implicit statement about the value of

their life as a disabled person. . . The way it’s received by disabled people, and certainly I think

the way many mentally ill people receive it, is

that it’s part of keeping them separate. It’s part

of saying, “You’re not really normal. For

instance, we don’t think you should have a family life with children. . .“

So, we have to be aware of what stigma in society has done, the high degree of defensiveness

that it has created to the kind of information that

we’re trying to bring and the sense that many

people have in the disability movement that

there’s a political undertone here of social control that is very, very worrisome. Having been so

recently released from second-class status, having so recently seen themselves as full participants, they’re very sensitive to anything that

would seem to discount their value as whole

people, real people, responsible people who can

and should make judgments for themselves

about their life.

The principle of nondirectiveness, so deeply

embedded in genetic counseling, opposes the eugenic interventions that consumers fear. Psychiatric geneticists generally spurn directive

counseling against childbearing as well, not only

out of respect for consumer autonomy, but also on

scientific grounds (27,28). “It needs to be said at

the outset that there is no place for public health

campaigns persuading people with psychiatric

disorder or a strong family history of psychiatric

disorder not to have children” (43). Recurrence

risk for family members is usually low for mental

disorders (except when both parents are afflicted,

for example, with schizophrenia). These conditions are often treatable. And the factors producing increased recurrence risk are not well

understood. Thus, the avoidance of childbearing

is not scientifically supportable as a means of primary prevention-eliminating mental disorders

from the population.

While experts largely eschew eugenic principles and directive counseling on reproductive

decisions for mental disorders, it would be dishonest to ignore the difficult, indeed imperfect,

translation of these principles into practice. In the

clinical realm, nondirective counseling, that does

not reveal the clinician’s own view of the burden

of illness or what best for the consumer, requires

considerable skill (4,8,46). Society’s negative

view of mental disorders also thwarts freedom of

reproductive choice (54,64). Possible stigmatization can influence the reproductive decisions by

creating a sense of public disapproval (see next

section). Secondarily, it may result in depleted

public resources and services for people with

mental disorders. Having a child with an increased

risk of a mental disorder, when services are inadequate for their care, is hardly an unhampered decision (50).

Many experts take explicit exception to nondirective counseling of people with a mental disorder when extremely disabled, raising questions

about decisionmaking and child-rearing capabilities. For women with severe mental disorders,

childbearing presents several other issues, including birth complications, potential teratogenic and

other negative effects of some psychotropic drugs

on offspring, the effect of pregnancy and the postpartum period on the mother’s mental disorder,

the mother’s ability to handle the additional stress

of raising a child, and the risk of adversely affecting the child’s development. One workshop participant, a primary and secondary consumer, noted
Chapter 3 implications for Society 143

that all too often a mother with a severe mental

disorder—in the midst of a symptom crisis—also

faces the loss of custody of her children, a devastating reality that might be avoided with parental

supports and adequate treatment (6). In light of

these concerns, a small body of research addresses

issues around family planning for women with severe mental disorders (17,33,44,53).

Workshop participants raised several other issues concerning genetic counseling and mental

disorders: 1) the provision of genetic services, 2)

multiple consumers of genetic counseling services, and 3) adoption and genetic counseling.

The provision of genetic services. While genetic counselors and mental health care providers

both have skills and expertise important for the

relay of information on the genetics of mental disorders, professionals in neither field are fully

trained to do so. Genetic counselors have knowledge of human genetics, are experienced in risk

communication, and are steeped in a professional

culture that respects individual autonomy. They

typically do not have expertise in mental disorder

diagnosis and treatment. Mental health care providers, on the other hand, offer expertise in the

diagnosis and treatment of mental disorders; their

knowledge of genetics and genetic counseling is

limited. Given the dearth of genetic counselors—

there are approximately 1,500 genetic counselors

in the United States, half of whom concentrate on

prenatal counseling (8)—the most realistic solution to this knowledge gap is the transfer of

competencies among professionals. Genetic

counselors and experts in medical genetics can

help educate mental health professionals about the

relay of genetic information; also, they may increasingly form partnerships with mental health

care providers.

Workshop participants noted another impediment to the delivery of genetic services: the way in

which it is financed. Private insurance rarely reimburses genetic counseling as an independent service (42,46). Thus, most genetic counseling

occurs in the context of a health care delivery

team. Also, the reimbursement system is not

geared to services that go both to an individual

with a disorder and their families. Finally, any extension of genetic counseling to people with mental disorders will have to ensure that expertise

reaches the public system of care, on which so

many individuals with the most severe conditions

rely.

Multiple consumers of genetic counseling

services. The client or consumer of genetic counseling services includes not only an individual

with a disorder, but also his or her family members

and prospective spouses. All have an interest and

may seek information on the inheritance of a

condition. One workshop panelist noted the tensions that exist (18): “I don’t have one client, I always have the family. So, I’m always juggling a

lot of different balls in terms of who am I actually

addressing, different issues for everybody in the

family.” Ideally, the provision of genetic information will not pit relatives, future spouses, and individuals with mental disorders against one another.

In practice, however, information on diagnosis

and the inheritance of mental disorders can lead to

serious interpersonal conflict as well as raise legal

and ethical concerns. In general, providers of genetic services try to balance their duties to maintain confidentiality-a primary but not absolute

concern in the eyes of the law—against disclosing

information, when confidentiality could cause

harm to a third party (2,30,58; see previous discussion).

Adoption and genetic counseling. It is not uncommon for women with severe psychiatric disorders to give up their children for adoption.

Prospective parents therefore may have an interest

in learning the risk for serious mental disorder in

their adopted offspring. One workshop panelist

indicated that “probably the most frequent call I

get is from a prospective adoptive parent who goes

through regular adoption agencies in the United

States and finds out that the child has a mother

with schizophrenia (19).” Adoptive parents face

barriers to information. In addition to the limited

number of professionals able to give genetic information on mental disorders, access to information on the mental health history of biological

parents may be lacking(11 ).
44 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

PUBLIC PERCEPTIONS AND

SOCIAL IMPLICATIONS

Research does not move forward in a social vacuum, simply unveiling new knowledge. Obviously,

biomedical research has as one primary goal the

improvement of clinical care. But the interface between research and society goes beyond clinical

practice. Scientific advances become the tools of

public opinion and social policy (51). Conversely,

the social perception of a scientific approach can

fuel popular support opposition. The subject

of the workshop-genetics and mental disorders—invokes powerful images and arouses intense public reactions. This section considers

public perceptions of genetics and mental disorders, how they intermingle, and some of the social

and public policy issues that emerge.

Molecular genetics has become a modem-day

celebrity (49,52). Featured on the front pages of

newspapers and popular magazines, molecular

genetics is often described as instruction manual,

crystal ball, and pharmacopoeia all rolled up into

one (for a recent example, see reference 23). This

air of expectation that surrounds genetic research

has led many commentators to express the hope

that human diseases will be vanquished and even

many social ills will be eliminated (16,37,40).

The general public apparently accepts this expectation, with national surveys showing enthusiasm for genetic testing and gene therapy (41).

Some analysts worry about the hyperbole and

value-laden symbols used to describe molecular

genetics. Genes are characterized as good or bad;

there are popular references to people “going

shopping” for genes when choosing a mate or

adopting a child; complex traits and behavior are

boiled down to DNA fragments. Many liken genetics with invariable or unchangeable characteristics. In an analysis of The Social Power of

Genetic Information, one workshop participant

characterized how gene-talk has infiltrated the

public’s psyche (49):

You can be sure that genetic ideas have been

popularized when you see a button saying “Gene

police! You—Out of the Pool”; or a Mother’s

Day card, to a daughter who is herself a mother,

that says on the front, “What a good Mother you

are,” and on the inside, “It’s all in the genes.”

Even the advertising industry seems to have assimilated genetic concepts: an ad for a BMW

boasts its “genetic advantage.”

Slogans by themselves are hardly dangerous.

But their influence on public attitudes may be, especially among people unfamiliar with genetic

principles—as is the norm (67). Perhaps most

ironically, expressed genetic “triumphalism,” as

the editor of the prestigious journal Nature termed

it (40), fuels a backlash against the very science it

once celebrated. A recent article in Time magazine

noted that “[t]here is already talk of a genetic

backlash, a revolt against the notion that we are

our genes, or, as one critic put it, ‘that our Genes R

Us’” (23). Data from surveys also convey public

fears and concerns about genetic testing and genetic engineering (23,41). Researchers of the genetics of mental disorders, who participated in the

OTA-NIMH workshop, described how just a few

years transformed them from scientific heroes to

pariahs among their peers (19). In a recent manuscript, a scientist who participated in the workshop notes that genetics is often equated with

Nazism. “Critics of this enterprise are quick to

associate contemporary strategies with the lurid

and disquieting past abuses of biology by the

Nazis, resulting in the sterilization or murder of

thousands of mental patients, the physically handicapped, and millions of ‘non-Aryans’ during the

Holocaust” (31). Similarly, a researcher into twins

who are discordant for schizophrenia notes in a recent text that he was “publicly called ‘anew Mengele’ by a psychiatrist at a national conference”

(60). He concludes that “[f]or a few people it

seems that anybody who studies twins is automatically assumed to be a fascist or worse” (60).

Withered support for research is not the only

worrisome result of exaggerated or simpleminded claims about genetics. The public’s perception of genetics is a primary thread in the fabric

of public policy. Many analysts express alarm at

the potential discriminatory use of genetic information, falsely perceived as forecasting a certain, unyielding, or completely incapacitating fate
(1,48). A preliminary case study describes some

of the discriminatory consequences of such viewpoints (9):

Genetic conditions are regarded by many social institutions as extremely serious, disabling,

or even lethal conditions without regard to the

fact that many individuals with “abnormal” genotypes will either be perfectly healthy, have

medical conditions which can be controlled by

treatment, or experience only mild forms of a

disease. As a result of this misconception, decisions by such institutions as insurance companies and employers are made solely on the basis

of an associated diagnostic label rather than on

the actual health status of the individual or family. . . Once labeled . . . an individual may suffer

serious consequences. . . These include inability to get a job, health insurance, or life insurance, being unable to change jobs or move to a

different state because of the possibility of losing insurance, and not being allowed to adopt a

child.

Genetic discrimination has received considerable attention from policy makers and analysts. In

fact, 5 percent of the National Institutes of

Health’s National Center for Human Genome Research budget—$5 million in fiscal year 1992—is

devoted to the task of addressing the Ethical, Legal, and Social Implications (ELSI) of genetic information (see chapter 1). Among the most

discussed issues are insurance and employment

discrimination on the basis of genetic test results

(box 3-3).

While genetic information and the perception

of genetics may serve to limit access to health

care, its social influence may be more insidious.

Public pressure may mount against individuals

viewed as passing on disease genes to their offspring. Citing survey results, a recent OTA report

concluded that “stigmatization of carriers [of the

gene for cystic fibrosis] is likely to focus on beliefs that it is irresponsible and immoral for people

who could transmit disability to their children to

reproduce” (64). In response to a 1990 general

population survey, 39 percent said “every woman

who is pregnant should be tested to determine if

Chapter 3 implications for Society 145

10 percent of those surveyed expressed the belief

that a woman should be required bylaw to have an

abortion rather than have the government help pay

for the child’s care. Public opinion may even turn

against bringing a child into the world with a benign genetic condition. The public response to TV

anchorwoman Bree Walker Lampley’s pregnancy

is illustrative. When she became pregnant with her

second child, she found herself the focus of Los

Angeles radio talk show attacks. Ms. Lampley has

a genetic condition-ectrodactyly-which manifests as the absence of one or more fingers or toes.

Because her offspring are at a 50 percent risk of inheriting the condition, the radio talk show callers

and host criticized Lampley’s pregnancy.

Mental disorders are among the most stigmatized of health conditions. Although attitudes toward mental disorders appear to be improving

(12,13), data continue to show that the public is

uneducated about mental disorders, fearful of it,

and hostile to people with these conditions

(63,66). For example, a recent national survey of

public attitudes toward people with disabilities

shows that from the public’s perspective mental

disorders are the most disturbing of all disabling

conditions (47). Many individuals harbor beliefs

that bad parenting, personal inadequacy, weakness of character, or sinfulness lie at the root of severe mental disorders (63). The news and

entertainment media promote these stigmatizing

views with their routine presentation of people

with mental disorders as incompetent, ineffectual,

and violent (63,66).

Ignorance and negative attitudes, combined

with other factors, wreak havoc on the lives of

people with mental disorders. Data from surveys

and other research show the tragic consequences:

people with severe mental disorders suffer poor

self-esteem and discrimination in employment,

housing, and access to health care (39,66).

The negative attitudes attached to mental disorders aggrieve family members as well. In addition

to becoming the most significant care-provider,

family members suffer psychological consethe baby has any serious genetic defect.” Nearly quences.
461 Mental Disorders and Genetics: Bridging the Gap Between Research and Society
Chapter 3 implications for Society 147

Subjective burden—the family’s distress

over the pain and altered life prospects of their

mentally ill relative—is exacerbated by these

stigmatizing events. Reactions to perceived social censure become intertwined with responses

to the sorrows and demands of the illness itself.

Emotional reactions to major mental illness in a

family member frequently include bewilderment, fear, denial, self-blame, sorrow, grieving,

and empathic suffering. The added perception

of stigma may elicit rage and resentment or intensify depression and social withdrawal (38).

It is on this stage of stigmatization and discrimination that the social influence of genetic models

of mental disorders will play out. What is or will

be the result of the co-mingling of public perceptions of genetics and mental disorders? Although

few research data address this issue, workshop

participants and other commentators describe the

complex blend of views. On an undercurrent of

fear, many primary and secondary consumers express relief and optimism concerning genetic research of mental disorders.

I think it’s a complex issue but if you look at

the kind of stigma that is most painful to people

who have chronic psychiatric disabilities, discovering the scientific substrate and the underpinnings of these disorders has been profoundly

destigmatizing, I would say, in the last decade.

And I think it will continue to function that way

(5).

Clinicians echo this perception, as the words of

Dr. Raymond DePaulo show (20):

Families . . . do express fears. But I think, by

and large, they’re greatly relieved right now that

we’re seriously going at this enterprise. And

they take hope, not just from the fact that Freud

was wrong and it isn’t mother’s fault, but even

more from the fact that people are seriously

working on finding the causes of these disorders.

Many people with mental disorders and their

families look forward to the results of genetic research, because it offers promise of improved understanding of their condition and hope for

improved treatment (70). The very image of mental disorders as biological—genetic—is viewed as

destigmatizing, thus offering comfort for some.

“Proliferation of biogenetic research findings. . .

has somewhat softened the older prejudices

against families (38).”

A note of caution was sounded at the OTANIMH workshop, in terms of the potential discriminatory consequences of genetic data and the

backlash against research described above (10):

I think that it’s quite right that in general . . .

families affected with mental disorders have a

great belief in the value of research . . . [that it

will] change their status for the better. And I

think that’s a realistic and hopeful and good

thing. I think that it must be tempered, however,

by a realistic appraisal of the immediate impacts

of that research. For instance, the results of research becoming diagnostic tools can have an

immediate negative impact on them, let’s say,

with employers or insurers or whatever, using

the information in a discriminatory way. The

other thing I would say is that. . . I think that

there’s an issue of how research gets transmitted

to the public as well. You know, I see a lot of

people who are in cystic fibrosis groups or whatever, who are disillusioned at some level with

research, with genetic research. It’s clearly true

in mental disorders as well. . . I think that there

has to be, within the research community, some

recognition that crummy linkage studies have

an impact and it’s not always so good.

Recognizing the destigmatizing influence of

genetics research, one workshop participant

evoked the lessons of history in his note of caution

(15):

There’s a two-edged sword here. One of the

roles of genetics in the 1980s has been to use genetics as a destigmatizing force. That is, the

ability to say that there are genes involved in a

disorder proves that it is more like heart disease

or cancer because it’s a physical disorder.

There’s something broken in your brain. In essence, it’s an assault on the Freudian determinism of parenting causing schizophrenia. That’s

very powerful. But at the same time, we’ve got a

carryover of genetic determinism from the past

where, after all, in Germany, it was the folks

with psychiatric disorders who were believed to

have the disorders for genetic reasons who were

the first victims of eugenics. . . So. . . we’ve got
48 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

a very strange mix of cross currents going on

here. We’ve got one social current that says “We

need genetics to de-stigmatize” but we seem to

have forgotten the history that suggests that genetics can be used as a label effect-once that label is imposed, it sticks and can be used against

the individual and family.

History teaches us that science and prejudice

can combine in ways ruinous to people with stigmatized conditions and their families. The history

of screening for sickle cell anemia in this country

provides one example (64). Sickle cell anemia impairs red blood cell flow through the circulatory

system, causing complications in organ systems

throughout the body. This painful, incurable, and

sometimes fatal genetic condition has a high incidence among African Americans, with one in 400

newborns having sickle cell anemia. One in 10 or

11 have the sickle cell trait. Individuals with the

sickle cell trait have a normal and healthy life but

if they marry another carrier can have a child with

sickle cell disease. A massive screening program

for sickle cell trait was undertaken in the 1970s, so

that couples could be informed of their risks of

having affected children. While at first glance,

screening programs offered an inexpensive benefit to African American citizens—indeed, most

laws were drafted and promoted by African American legislators at the height of the civil rights

movement-early programs suffered from misinformation and discrimination against carriers.

Some state statutes consistently contained blatant

medical and scientific errors. Almost every state

law failed to insist on using the most sensitive

assay available. Controversy also focused on the

racial distribution of sickle cell mutations and the

target screening population. The laws were seen

by many citizens as racist eugenic measures aimed

at reducing the number of marriages between carriers and decreasing the number of pregnancies at

risk for affected children of a minority population.

The fact that the programs were largely designed

and operated by Caucasians fueled fears of genocide. Most state laws failed to provide adequate

education and counseling for persons with sickle

cell anemia or the trait. Those diagnosed with

sickle cell trait were often told they should not

have children, that childbirth would be hazardous,

or other untruths. State laws also failed to provide

public education to guard against discrimination

and stigmatization. Stories of job and insurance

discrimination multiplied as screening programs

proliferated. Other screening programs have had

similar consequences for the insurability and employability of those identified as predisposed to

genetic conditions (51).

The eugenics movement earlier this century offers an even more terrifying example of the potentially dangerous mix between genetics and

prejudice against mental disorders. In Nazi Germany and the United States, people with mental

disorders were among the initial targets of eugenic

policies (22,26,30,45). A number of scientific discoveries planted the seeds of eugenic policies in

the 19th and 20th centuries. Sir Francis Galton, a

cousin of Darwin who coined the term eugenics,

observed that many accomplished men of his day

were linked by bloodlines, which led to his belief

that proper matings could produce a race with enhanced intellectual, behavioral, and physical characteristics—positive eugenics. In addition,

Galton and others developed statistical techniques

that permitted the quantitative analysis of inherited traits. Social, political, and economic factors

fertilized the growth of the eugenics movement.

National attention was increasingly focused on

social issues of unemployment, criminality, prostitution, and chronic alcoholism. Also, concerns

arose that increased immigration from southern

and eastern Europe was drawing the United States

away from its “Anglo-Saxon superiority.”

Public policies executed these scientific and

social developments. At the federal level, eugenic

policies took the form of increasingly restrictive

immigration laws. Eugenicists, asserting the simple inheritance of such traits as lunacy, epilepsy,

alcoholism, pauperism, criminality, and feeblemindedness, proffered scientific rationales for excluding individuals from entry to the United

States. While authentic advances in genetics seeded the eugenics movement, they provided no evidence for the simple inheritance of the traits

mentioned above. Eugenic considerations also
Chapter 3 implications for Society 149

prompted states to enact laws regarding compulsory sterilization. In 1907, Indiana passed the first

law legalizing the compulsory sterilization of inmates at the state reformatory. By 1931, 30 states

had passed compulsory sterilization laws applying to individuals categorized as feeble-minded,

alcoholic, epileptic, sexually deviant, or mentally

ill. Individuals with mental disorders made up half

of the 64,000 persons in this country sterilized for

eugenic reasons between 1907 and 1964. When

eugenic sterilization laws were challenged in

1927, the U.S. Supreme Court ruled the practice

constitutional.

Many consider that the current application of

immigration and compulsory sterilization laws

suggests that eugenics is no longer a major concern. Furthermore, the understanding that mental

disorders do not have a simple genetic basis and

that nongenetic factors play an important role

would seem to limit the potential of eugenic policies. Perhaps most important, American repulsion

by the Nazi legacy and the emphasis in this country on individual reproductive rights also make

state-determined eugenic policies unlikely. But,

as noted above, indirect pressure not to have children may well come to bear on individuals seen to

have a greater genetic risk of mental disorders; society may brand them irresponsible or immoral for

transmitting disorders to their children. And eugenic policies are moving forward abroad. In China, a draft law on “eugenics and health protection”

presented to the Eighth National People’s Congress (NPC) in 1993 proposed that people with

diseases such as mental illness “which can be

passed on through birth” be banned from marrying (21 ).

SUMMARY AND CONCLUSIONS

People with mental disorders and their families

participate in research, benefit from its results,

and feel the impact of its social dissemination.

Workshop participants discussed these clinical

and social implications of research of the genetics

of mental disorders. At least three issues stand at

the fore of any attempt to bridge the gap between

research and society: family involvement, the

nature of mental disorders, and the need for

education.

Involvement of family members. Historically, ethical guidelines and public policy largely

have focused on the well-being of the individual,

as research participant, consumer of clinical services, and member of society. Genetic research

broadens this approach, extending the circle of

concern to family members in addition to the afflicted individual. Family members are necessary

participants in research raising issues around consent and confidentiality. Family members often

seek information on genetic status, which raises

potential conflicts. Any social effect of genetic research-for example, its use to limit access to

health care—will obtrude on individuals with

mental disorders and family members alike.

While workshop participants recognized the potential clash of interests between family members

and affected individuals, many expressed the belief that a framework of benevolence could lead to

relevant guidance for research, clinical practice,

and public policy-developments that are sorely

needed.

The nature of mental disorders. Two features

of mental disorders color genetic research and its

translation into practice and policy. First, mental

disorders can sometimes circumscribe an individual’s decisionmaking ability. The impact of some

mental disorder symptoms raises issues around

informed consent for research participation and

informed clinical decisionmaking. Advocating

the importance of individual autonomy, workshop

panelists strongly asserted the need to take seriously and perhaps foster further guidelines and

policies that increase the meaningful participation

of people with mental disorders in research and

clinical care, so as to better protect their rights and

well-being.

The second feature of mental disorders that permeates genetic research is the stigma attached to

these conditions. The ignorance and negative attitudes attached to mental disorders encumber research and clinical care, heightening concerns

about confidentiality. The stigma also drives support for this research among many consumers,
50 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

and, paradoxically, could fuel its abusive application. This social reality animates the final issue

put forth by workshop participants: the need for

education.

Educational needs extend to several spheres.

Researchers and individuals participating in the

review of research need information about the

clinical and ethical issues raised by research of the

genetics of mental disorders. Mental health care

providers need information about the genetics of

mental disorders and the practice of delivering

such information to requesting consumers. Similarly, genetic counselors need information on the

nature, diagnosis, and treatment of mental disorders. Finally, society at large needs information

about the nature of genetics and mental disorders,

in order to diminish fears and stigmatization and

to help inoculate against discriminatory policies.

CHAPTER 3 REFERENCES

1. Allen, W., and Ostrer, H., “Anticipating Unfair Uses of Genetic Information,” American

Journal of Human Genetics 53:16-21, 1993.

2. Andrews, L. B., ’’Legal Aspects of Genetic Information,” The Yale Journal of Biology and

Medicine 64:29-40, 1991.

3. Appelbaum, P. S., A.F. Zeleznik Professor of

Psychiatry and Director, Law and Psychiatry

Program, University of Massachusetts Medical Center, Worcester, MA, personal communication, July 11, 1994.

4. Bartels, D. M., LeRoy, B. S., and Caplan, A.L.

(eds.), Prescribing Our Future: Ethical Challenges in Genetic Counseling (New York,

NY: Aldine de Gruyter, 1993).

5. Bean, M. A., Vice President, Virginia Alliance for the Mentally Ill, and Chair, Virginia

Mental Health Consumers’ Association,

Richmond, VA, remarks at “Understanding

the Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

6. Bean, M. A., Vice President, Virginia Alliance for the Mentally Ill, and Chair, Virginia

Mental Health Consumers’ Association,

Richmond, VA, personal communication,

July 21, 1994.

7. Berg, K., and Kirch, D.G., National Institute

of Mental Health, National Institutes of

Health, “Genetic Counseling in Psychiatry,”

draft, 1992.

8. Biesecker, B. B., Genetic Counselor, National

Center for Human Genome Research, National Institutes of Health, Bethesda, MD, remarks at “Understanding the Role of Genetic

Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Office of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

9. Billings, P.R., Kohn, M. A., de Cuevas, M., et

al., “Discrimination as a Consequence of Genetic Testing,” American Journal of Human

Genetics 50:476-482, 1992.

10. Billings, P. R., Chief Medical Officer, Department of Veterans’ Affairs Medical Center,

Palo Alto, CA, remarks at “Understanding the

Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

11. Blair, D. M. B., ’’Lifting the Genealogical Veil:

A Blueprint for Legislative Reform of the

Disclosure of Health-Related Information in

Adoption,” North Carolina Law Review 70:

681-779, 1992.

12. Burgmann, F. D., Executive Vice President,

National Depressive and Manic-Depressive

Association, Chicago, IL, personal communication, July 30, 1994.

13. Clements, M., “What We Say About Mental

Illness,” Parade Magazine, Oct.31, 1993, pp.

4-6.

14. Conneally, P. M., Distinguished Professor of

Medical Genetics and Neurology, Indiana
Chapter 3 implications for Society 151

15.

16.

17.

18.

19.

20.

University School of Medicine, Indianapolis,

IN, remarks at “Understanding the Role of

Genetic Factors in Mental Illness: Bridging

the Gap Between Research and Society,” a

workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Jan. 21-22, 1993.

Cook-Deegan, R. M., Director, Division of

Bio-Behavioral Sciences and Mental Disorders, Institute of Medicine, Washington, DC,

remarks at “Understanding the Role of Genetic Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Office of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

Cook-Deegan, R. M., The Gene Wars: Science, Politics, and the Human Genome (New

York, NY: W.W. Norton& Co., 1994).

Coverdale, J. H., Bayer, T. L., McCullough,

L. B., et al., “Respecting the Autonomy of

Chronic Mentally Ill Women in Decisions

About Contraception,” Hospital and Community Psychiatry 44;671-674, 1993.

Cox, D. R., Professor, School of Medicine,

Stanford University, Palo Alto, CA, remarks

at “Understanding the Role of Genetic Factors

in Mental Illness: Bridging the Gap Between

Research and Society,” a workshop sponsored

by the Office of Technology Assessment and

the National Institute of Mental Health,

Washington, DC, Jan. 21-22, 1993.

DeLisi, L. E., Professor of Psychiatry, Research Foundation SUNY, remarks at “Understanding the Role of Genetic Factors in

Mental Illness: Bridging the Gap Between

Research and Society,” a workshop sponsored

by the Office of Technology Assessment and

the National Institute of Mental Health,

Washington, DC, Jan. 21-22, 1993.

DePaulo, J. R., Associate Professor, Johns

Hopkins University, School of Medicine,

Baltimore, MD, remarks at “Understanding

the Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

Dickson, D., “Concern Grows Over China’s

Plans To Reduce Number of ‘Inferior

Births,’” Nature 367:3, 1994.

Duster, T., Backdoor to Eugenics (New York,

NY: Routledge, 1990).

Elmer-Dewitt, P., “The Genetic Revolution,”

Time, Jan. 17, 1994, pp. 46-53.

Flynn, L., Executive Director, National Alliance for the Mentally Ill, Arlington, VA, remarks at “Understanding the Role of Genetic

Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Office of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

Frankel, M. S., and Teich, A.H. (eds.), The

Genetic Frontier: Ethics, Law, and Policy

(Washington, DC: American Association for

the Advancement of Science, 1993).

Garver, K. L., and Garver, B., “Eugenics: Past,

Present, and Future,” American Journal of

Human Genetics 49: 1109-1118, 1991.

Gershon, E. S., “Genetics,” Manic-Depressive Illness, F.K. Goodwin and K.R. Jamison

(New York, NY: Oxford University Press,

1990).

Gershon, E., Chief, Clinical Neurogenetics

Branch, National Institute of Mental Health,

National Institutes of Health, Bethesda, MD,

remarks at “Understanding the Role of Genetic Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Office of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

Gottesman, 1.1, Schizophrenia Genesis: The

Origins of Madness (New York, NY: W.H.

Freeman, 1991).

Gottesman, 1.1., Professor, University of Virginia, Charlottesville, VA, remarks at “Understanding the Role of Genetic Factors in

Mental Illness: Bridging the Gap Between

Research and Society,” a workshop sponsored

by the Office of Technology Assessment and
52 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

the National Institute of Mental Health,

Washington, DC, Jan. 21-22, 1993.

31. Gottesman, 1.1., “Schizophrenia Epigenesis:

Past, Present, and Future,” Acta Psychiatric

Scandinavia, in press.

32. Grisso, T., and Appelbaum, P. S., “Mentally

Ill and Non-Mentally-Ill Patients’ Abilities

To Understand Informed Consent Disclosures

for Medication,” Law and Human Behavior

15:377-388, 1991.

33. Grunebaum, H. U., Abemethy, V. D., Rofman,

E. S., et al., “The Family Planning Attitudes,

Practices, and Motivations of Mental Patients,” American Journal of Psychiatry 128:

740-744, 1971.

34. Honberg, R., Legal Advocate, National Alliance for the Mentally Ill, Arlington, VA, remarks at “Understanding the Role of Genetic

Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Office of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

35. Institute of Medicine, Assessing Genetic

Risks: Implications for Health and Social

Policy (Washington, DC: National Academy

Press, 1993).

36. Jamison, K. R., Touched With Fire(New York,

NY: The Free Press, 1993).

37. Keller, E. F., “Nature, Nurture, and the Human

Genome Project,” The Code of Codes: Scientific and Social Issues in the Human Genome

Project, D.J. Kevles and L. Hood (eds.)

(Cambridge, MA: Harvard University Press,

1992).

38. Lefley, H. P., “The Stigmatized Family,” Stigma and Mental Illness, P.J. Fink and A. Tasman (eds.) (Washington, DC: American

Psychiatric Press, Inc., 1992).

39. Link, B. G., “Understanding Labeling Effects

in the Area of Mental Disorders: An Assessment of the Effects of Expectations of Rejection,” American Sociological Review 52:96-

112, 1987.

40. Maddox, J., “Willful Public Misunderstanding of Genetics,“ Nature 364:281, 1993.

41. March of Dimes Birth Defects Foundation,

Genetic Testing and Gene Therapy: National

Survey Findings, Washington, DC, September 1992.

42. Marks, J. H., Director, Human Genetics Program, Sarah Lawrence College, Bronxville,

NY, remarks at “Understanding the Role of

Genetic Factors in Mental Illness: Bridging

the Gap Between Research and Society,” a

workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

43. McGuffln, P., Owen, M.J., O’Donovan,

M. C., et al., Seminars in Psychiatric Genetics

(London, England: Gaskell, 1994).

44. McCullough, L. B., Coverdale, J., Bayer, T.,

et al., “Ethically Justified Guidelines for Family Planning Interventions To Prevent Pregnancy in Female Patients With Chronic

Mental Illness,” American Journal of Obstetrics and Gynecology 167: 19-25, 1992.

45. Meyer, J.-E., “The Fate of the Mentally Ill in

Germany During the Third Reich,” Psychological Medicine 18:575-581, 1988.

46. Murray, R.J., Jr., Professor, Howard University College of Medicine, Washington, DC, remarks at “Understanding the Role of Genetic

Factors in Mental Illness: Bridging the Gap

Between Research and Society,” a workshop

sponsored by the Oflice of Technology Assessment and the National Institute of Mental

Health, Washington, DC, Jan. 21-22, 1993.

47. National Organization on Disability, “Public

Attitudes Toward People With Disabilities,”

survey conducted by Louis Harris and

Associates, Inc. (Washington, DC: 1991).

48. Natowicz, M. R., Alper, J. K., and Alper, J. S.,

“Genetic Discrimination and the Law,’ American Journal of Human Genetics 50:465-475,

1992.

49. Nelkin, D., “The Social Power of Genetic Information,” The Code of Codes: Scientic

and Social Issues in the Human Genome Project, D.J. Kevles and L. Hood (eds.) (Cambridge, MA: Harvard University Press, 1992).
Chapter 3 implications for Society 153

50. Nelkin, D., Professor, New York University,

New York, NY, remarks at “Understanding

the Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

51. Nelkin, D., and Tancredi, L., Dangerous

Diagnostics: The Social Power of Biological

Information, 2nd Ed. (Chicago, IL: University of Chicago Press, 1994).

52. Nelkin, D., and Lindee, S., The Imagined

Gene: DNA in American Popular Culture

(New York, NY: W.H. Freeman, in press).

53. Packer, S., “Family Planning for Women

With Bipolar Disorder,” Hospital and Community Psychiatry 43:479-481, 1992.

54. Restinas, J., “The Impact of Prenatal Technology Upon Attitudes Toward Disabled Infants,” Research in the Sociology of Health

Care 9:75-102, 1991.

55. Schulz, P. M., Schulz, S. C., Dibble, E., et al.,

“Patient and Family Attitudes About Schizophrenia: Implications for Genetic Counseling,” Schizophrenia Bulletin 8:504-513,

1982.

56. Shore, D., Berg, K., Wynne, D., et al., “Legal

and Ethical Issues in Psychiatric Genetic Research,” American Journal of Medical Genetics (Neuropsychiatric Genetics) 48: 17-21,

1993.

57. Shore, D., Director, Schizophrenia Research

Branch, National Institute of Mental Health,

Rockville, MD, remarks at “Understanding

the Role of Genetic Factors in Mental Illness:

Bridging the Gap Between Research and Society,” a workshop sponsored by the Office of

Technology Assessment and the National

Institute of Mental Health, Washington, DC,

Jan. 21-22, 1993.

58. Suter, S. M., “Whose Genes Are These Anyway’?: Familial Conflicts Over Access to Genetic Information,” Michigan Law Review

91: 1854-1908, 1993.

59. Targum, S. D., Dibble, E. D., Davenport, Y. B.,

et al., “The Family Attitudes Questionnaire:

Patients’ and Spouses’ Views of Bipolar Illness,” Archives of General Psychiatry 38:

562-568, 1981.

60. Torrey, E. F., Bowler, A. E., Taylor, E. H., et al.,

Schizophrenia and Manic-Depressive Disorder: The Biological Roots of Mental Illness as

Revealed by the Landmark Study of Identical

Twins (New York, NY: Basic Books, 1994).

61. Tsuang, M. T., “Genetic Counseling for Psychiatric Patients and Their Families,” American Journal of Psychiatry 135: 1465-1475,

1978.

62. Tsuang, M.T., and Faraone, S. V., The Genetics of Mood Disorders (Baltimore, MD: The

Johns Hopkins University Press, 1990).

63. U.S. Congress, Office of Technology Assessment, The Biology of Mental Disorders, OTABA-538 (Washington, DC: U.S. Government

Printing Office, September 1992).

64. U.S. Congress, Office of Technology Assessment, Cystic Fibrosis and DNA Tests:

Implications of Carrier Screening, OTABA-532 (Washington, DC: U.S. Government

Printing Office, August 1992).

65. U.S. Congress, Office of Technology Assessment, Biomedical Ethics in U.S. Public

Policy-Background Paper, OTA-BPBBS-105 (Washington, DC: U.S. Government Printing Office, June 1993).

66. U.S. Congress, Office of Technology Assessment, Psychiatric Disabilities, Employment,

and the Americans With Disabilities Act,

OTA-BP-BBS-124 (Washington, DC: U.S.

Government Printing Office, March 1994).

67. U.S. Department of Energy, Los Alamos Science, The Human Genome Project Number

20, 1992.

68. U.S. Department of Health, Education, and

Welfare, National Commission for the Protection of Human Subjects of Biomedical and

Behavioral Research, The Belmont Report:

Ethical Principles and Guidelines for the

Protection of Human Subjects of Research
54 I Mental Disorder’ sand Genetics: Bridging the Gap Between Research and Society
Appendix A:

Workshop

Participants’ A

Herbert Paroles

(Workshop Chair)

College of Physicians and

Surgeons

Columbia University

New York, NY

Mary Ann Bean

Virginia Mental Health

Consumers’ Association

National Alliance for the

Mentally Ill

Richmond, VA

Barbara Bowles Biesecker

National Center for Human

Genome Research

National Institutes of Health

Bethesda, MD

Paul R. Billings

California Pacific Medical

Center

San Francisco, CA

P. Michael Conneally

Indiana University School of

Medicine

Indianapolis, IN

Robert M. Cook-Deegan

Institute of Medicine

Washington, DC

David R. Cox

University of California,

San Francisco

San Francisco, CA

Lynn E. DeLisi

Research Foundation SUNY

Stony Brook, NY

J. Raymond DePaulo

Johns Hopkins University

Baltimore, MD

Laurie Flynn

National Alliance for the

Mentally Ill

Arlington, VA

Susan Folstein

Johns Hopkins University

Baltimore, MD

I 55
56 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Elliot S. Gershon

National Institute of Mental

Health

National Institutes of Health

Bethesda, MD

Conrad Gilliam

College of Physicians and

Surgeons

Columbia University

New York, NY

Alison Goate

Washington University

St. Louis, MO

Irving 1. Gottesman

University of Virginia

Charlottesville, VA

Ron Honberg

National Alliance for the

Mentally Ill

Arlington, VA

Robert F. Murray, Jr.

Howard University

Washington, DC

Dorothy Nelkin

New York University

New York, NY

Neil J. Risch

Yale University School of

Medicine

New Haven, CT

S. Charles Schulz

Case Western Reserve University

Cleveland, OH

David Shore

National Institute of Mental

Health

National Institutes of Health

Bethesda, MD

Ming T. Tsuang

Harvard School of Medicine

Brockton West Roxbury VA

Medical Center

Brockton, MA

Michelle Walsh

National Depressive and

Manic-Depressive Association

Chicago, IL

Myrna Weissman

College of Physicians and

Surgeons

New York State Psychiatric

Institute

Columbia University

New York, NY

Joan H. Marks

Sarah Lawrence College

Bronxville, NY
review of a draft of this background paper.

Paul S. Applebaum Frank D. Burgmann

University of Massachusetts National Depressive and

Medical Center Manic-Depressive Association

Worcester, MA Chicago, IL

Mary Ann Bean P. Michael Conneally

Virginia Mental Health Indiana University School of

Consumers’ Association Medicine

National Alliance for the Indianapolis, IN

Mentally Ill

Richmond, VA Robert M. Cook= Deegan

Institute of Medicine

Barbara Bowles Biesecker Washington, DC

National Center for Human

Genome Research Lynn E. DeLisi

National Institutes of Health Research Foundation SUNY

Bethesda, MD Stony Brook, NY

J. Raymond DePaulo

Johns Hopkins University

Baltimore, MD

Susan Folstein

New England Medical Center

Boston, MA

Elliot S. Gershon

National Institute of Mental

Health

National Institutes of Health

Bethesda, MD

Alison Goate

Washington University

St. Louis, MO

I 57
.

58 I Mental Disorders and Genetics: Bridging the Gap Between Research and Society

Irving L Gottesman

University of Virginia

Charlottesville, VA

Kay Redfield Jamison

Johns Hopkins University

Baltimore, MD

Joan H. Marks

Sarah Lawrence College

Bronxville, NY

Dorothy Nelkin

New York University

New York, NY

Philip R. Reilly

Shriver Center for Mental

Retardation, Inc.

Waltham, MA

Neil J. Risch

Yale University School of

Medicine

New Haven, CT

David Shore

National Institute of Mental

Health

National Institutes of Health

Bethesda, MD

Ming T. Tsuang

Harvard School of Medicine

Brockton West Roxbury VA

Medical Center

Brockton, MA

Myrna Weissman

College of Physicians and

Surgeons

New York State Psychiatric

Institute

Columbia University

New York, NY

Herbert Paroles

College of Physicians and

Surgeons

Columbia University

————————————— —

Superintendent of Documents Publications Order Form

Order Processing Code:

“7530

❑ YES, please send me the following:

Telephone orders (202) 512- 18&3

(The best time to call is between 8-9 a.m. EST.)

To fax your orders (202)512-2250

Charge your order. It’s Easy!

copies of Mental Disorders and Genetics: Bridging the Gap Between Research and Society

(64pages) SIN 052-003 -01392-4 at $4.25 each.

The total cost of my order is $ . International customers please add 2590. Prices include regular domestic

postage and handling and are subject to change.

(Company or Personal Name) (Please type or print)

(Additional address/attention line)

(Street address)

(City, State, ZIP Code)

Please Choose Method of Payment:

❑ Check Payable to the Superintendent of Documents

(Daytime phone including area code)

(Purchase Order No.)

(Authorizing Signature) (9/94)

YES NO

May we make your name/address available to other mailers? ❑ ❑

Mail To: New Orders, Superintendent of Documents, P.O. Box 371954, Pittsburgh, PA 15250-7954

THIS FORM MAY BE PHOTOCOPIED