IACAPAP Textbook of Child and Adolescent Mental Health

INTRODUCTION

Chapter
A.13

WHAT CHILD MENTAL HEALTH
PROFESSIONALS SHOULD KNOWABOUT GENETICS
Robert R. Althoff

Robert R. Althoff MD, PhD
Jérôme Lejeune(1926–1994),
a French
pediatrician
and geneticist,
discovered thatthe presence of allor part of an extra
chromosome 21
was the cause of
Down syndrome.

Associate Professor of
Psychiatry, Psychology and
Pediatrics & Director, Divisionof Behavioral Genetics,
Vermont Center for Children,
Youth & Families, University ofVermont College of Medicine,
Burlinton, US
Conflict of interest: none
disclosedThis publication is intended for professionals training or practicing in mental health and not for the general public. The opinions
expressed are those of the authors and do not necessarily represent the views of the Editor or IACAPAP. This publication seeks todescribe the best treatments and practices based on the scientific evidence available at the time of writing as evaluated by the authorsand may change as a result of new research. Readers need to apply this knowledge to patients in accordance with the guidelines andlaws of their country of practice. Some medications may not be available in some countries and readers should consult the specific drug
information since not all dosages and unwanted effects are mentioned. Organizations, publications and websites are cited or linked toillustrate issues or as a source of further information. This does not mean that authors, the Editor or IACAPAP endorse their content
or recommendations, which should be critically assessed by the reader. Websites may also change or cease to exist.
©IACAPAP 2016. This is an open-access publication under the Creative Commons Attribution Non-commercial License. Use,
distribution and reproduction in any medium are allowed without prior permission provided the original work is properly cited andthe use is non-commercial.
Suggested citation: Althoff RR. What child mental health professionals should know about genetics. In Rey JM (ed), IACAPAP
e-Textbook of Child and Adolescent Mental Health. Geneva: International Association for Child and Adolescent Psychiatry and Allied
Professions 2016.

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1IACAPAP Textbook of Child and Adolescent Mental HealthOver the past 20 years, the field of child and adolescent psychiatry
has benefitted from advances in behavioral and molecular genetics.
While child psychiatric conditions were once assumed to be caused bymechanisms such as “fixation” in a particular phase of development or “refrigerator
mothers”, the discovery of the familiality and heritability of these disorders
has made it less fashionable to argue against the biological underpinnings ofdevelopmental psychopathology. On the other hand, most clinicians are primarilytaught genetics based on single gene, Mendelian inheritance. Because this kind of
one-gene-one-disorder inheritance is relatively rare in child psychopathology, there
has been a perception that psychiatric genetics is not moving fast enough to findthe causes of child psychiatric conditions. Indeed, if ADHD, autism, or bipolar
disorder in children were caused by a single gene, it would have been found by
now. Instead, child psychiatric disorders are prime examples of complex traits. A
complex trait is one that does not follow simple Mendelian inheritance, but rather
is associated with multiple genes (and, likely, multiple environments) operating
together.

James Watson andFrancis Crick, together
with Maurice Wilkins,were awarded the 1962
Nobel Prize in Medicine
for their discovery of thestructure of DNA. Click on
the image to view James
Watson relate the frankand funny story of how
he and Francis Crick,discovered the structure of
DNA (20:54).

To help make sense of child psychiatric genetics, we will first introduce
the basic concepts of genetics. This will serve as a brief primer in the way thatmental health problems are passed from parent to child. We will then discuss
the importance of examining families in an empirical way such that information
about both the genetics and the environment of the family can be ascertained.
Then, we will describe the different types of research studies in genetics and how
to interpret them. This leads naturally into a discussion of the differences between
single gene (Mendelian) and polygene (complex) disorders. We will then discuss
what genetic tests may be appropriate for these conditions in clinical practice andwhen genetic counseling is appropriate.

Is there a term that you
don’t know? Click on theimage to find a description
and images of common
genetic terms

Each cell in the human body (except red blood
cells) contains 23 pairs of chromosomes.
Chromosomes are inherited: each parent
contributes one chromosome per pair to theirchildren. (a) Each chromosome is made up of
a tightly coiled strand of DNA. When uncoiled
it reveals (b) the familiar double-helix shape. If
we picture DNA as a twisted ladder, the sides,
made of sugar and phosphate molecules, areconnected by (c) rungs made of chemicals calledbases—adenine (A), thymine (T), guanine (G),and cytosine (C)—that form interlocking pairs.
The order of these bases along the length of theladder is called the DNA sequence.
E Branscomb.

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2

IACAPAP Textbook of Child and Adolescent Mental HealthBASIC GENETIC CONCEPTS
Central to psychiatric genetics is the fundamental notion that in the
nucleus of the cell, deoxyribonucleic acid (DNA) is transcribed into messenger
ribonucleic acid (mRNA), which is then translated in the ribosome via transfer
RNA (tRNA) into protein. Proteins do the work of the cell – being transported inand out of the cell membrane to serve as receptors for neurotransmitters, changing
the way that the cell fires, serving as messengers for other biological systems, etc.
This central dogma of biology that DNA ->RNA -> protein provides the basis forall other associations that we will discuss. Because the proteins in neurons start
first as a basic code in DNA, the way that neurons function can be affected by
the variation in the DNA code. Further, because DNA in each cell is, at least in
structure, essentially the same pattern of nucleotide base pairings, one need notlook at neurons directly to make these associations. DNA taken from any cell inthe body (although most frequently from blood lymphocytes or cheek/salivary
epidermal tissue) can provide insight into the DNA sequence throughout therest of the body. If a change in the DNA code is associated differentially with a
psychiatric condition, one would be a step closer to understanding the biologicalsystem that undergirds that condition.
One other key concept is necessary here to make it clear why we examine
DNA in child psychiatry. DNA is passed on from parent to child. DNA is adouble stranded molecule that contains one strand from one parent and a second
strand from the other parent. On each of these strands, or chromatids, are stringsof nucleotides, some of which cluster into functional units, or genes, that codefor protein. Other parts of the chromatid are intragenic or in-between genes. These
regions themselves may also be important to the function of proteins, possibly
indirectly. Both genes and intragenic regions are passed from parent to child.
Genes often come in two forms, called alleles. A child, therefore, receives one allele
from his or her father and another allele from his or her mother. Thus, if one were
to determine that specific alleles of a gene follow along with a particular disorder
within a family, one could derive associations between specific genes and specificdisorders.
Because half of the DNA in an individual is transmitted from the motherand half from the father, this has enabled clinicians and researchers to be able todetermine specific inheritance patterns for particular single gene disorders. For
example, Huntington Chorea is inherited due to an expansion in the number

ALLELEAn allele is an alternative
form of a gene (onemember of a pair) thatis located at a specificposition on a specificchromosome. These
DNA codings determine
distinct traits that can bepassed on from parents
to offspring. Individuals
inherit two alleles for eachgene, one from eachparent. If the two alleles
are the same, the individualis homozygous for thatgene. If the alleles aredifferent, the individual isheterozygous. In traditional
Mendelian genetics,
alleles can be dominantor recessive. Under
this model, if a trait isinfluenced only by a single
gene, an organism that isheterozygous at a specificlocus—and, therefore,
carries one dominant and
one recessive allele—will
express the dominantphenotype. Alleles
contribute to the organism’s
phenotype, which is theoutward appearance ofthe organism. Alleles are
divided into the “major” andthe “minor” allele basedon the allele of a gene thatmost frequently occurs
in the population. Alleles
are considered “common”
if they occur more often
than 1% in a population.
Otherwise, they are
considered “rare”.

KARYOTYPE
A karyotype is the number and appearance of chromosomes in the nucleus of a cell. The
term is also used to denote the complete set of chromosomes in an individual organism.
Karyotypes describe the chromosome countof an organism, and what these chromosomes
look like under a light microscope: length, theposition of the centromeres, differences between
the sex chromosomes, and any other physicalcharacteristics. The figure on the left shows the
karyotype of a normal human male, while theone on the right is the karyotype of a person with
Down syndrome.

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3IACAPAP Textbook of Child and Adolescent Mental Health

DESCRIBING THE LOCATION OF A
GENE
When loci on a chromosome are described,
they are described using the nomenclature of
the chromosome number, followed by the armof the chromosome. Chromosomes are madeof two chromatids and have a long and a shortarm on either side of the centromere, whichholds the two chromatids together. The p arm
is the short arm – which was annotated forbeing the petit arm. The q arm is the long arm– which was annotated for being the letter that
follows “p”. In the nomenclature, the arm is thenfollowed by a series of numbers corresponding
to position by region, band, and then sub-band.
In this case, 4p16.3 designates the short armof chromosome 4, region 1, band 6, sub-band
3. In the figure, the CFTR gene (cystic fibrosis
transmembrane conductance regulator) is
located on the long arm of chromosome 7 atposition 7q31.2.

Image: U.S. National Library of Medicine

NAMING GENESof specific tri-nucleotide repeats at a particular area of the genome (4p16.3).
This region of the chromosome is inherited from parent to child with worsening
symptoms in each subsequent generation due to the accumulation of more
repeats. Because of this inheritance pattern, the familiality was first established byexamining and plotting out the histories of families with Huntington (see Figure
A.13.1). This was followed by discovery of the pertinent chromosome, after whicha particular gene in that region was identified. True to the central dogma above,
this gene — huntingtin — codes for the huntingtin protein which plays a role in
the pathogenesis of Huntington chorea.

Genes are named bythose who discover themand are frequently given
colorful names, such as thissituation where the gene isassociated with Huntington
Chorea, but the gene isspelled huntingtin. Genes
are typically written in lower
case lettering in italics.

Figure A.13.1. Pedigree* of a family demonstrating a heritable trait.

*In pedigrees, circles represent females, squares represent males.
Circles and squares are filled if that individual is affected by the trait
being diagramed. Horizontal lines connecting individuals represent
a mating pair. Vertical lines represent the offspring of that mating
pair.

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4IACAPAP Textbook of Child and Adolescent Mental Health

GENETICS OF CHILD PSYCHIATRIC DISORDERS
For most child psychiatric disorders, however, the Mendelian pattern does
not hold. Instead, child and adolescent psychiatric disorders are related to genetics
in one of three scenarios, which are not mutually exclusive:•

The common disease-common variant hypothesis•

The rare-variant-common disease hypothesis; and•The gene-environment interaction hypothesis.

Because each of these hypotheses has stemmed from, and has led to, slightly
different approaches in the literature, we review them each briefly.

The Common Disease-Common Variant Hypothesis
In this hypothesis, child psychiatric disorders are due to the accumulationof multiple common genes, each of which has a minor additive effect on thepresentation of the illness. In this hypothesis, genes which may otherwise havebeen selected against through natural selection are kept in the population because
in other environments and in combination with certain other genes they areadvantageous. When enough of the risk alleles are put together, however, thecombined effect pushes the child towards a particular disorder. Support for thishypothesis comes from findings like those of Constantino et al (2010) who
showed using quantitative measurement that subsyndromal autistic traits arefound in siblings of individuals with autism. Similar arguments have been madefor ADHD. This suggests that there is a familial aggregation of genes that affect theindividual, but one individual has an overall higher dose of them. Further support
for this hypothesis comes from findings in the literature of combined additive
genetics of disorders (as we will see below under “twin studies” and “genome-wide
complex trait analysis”). Consistent with this has also been the relatively minimal
findings of genes of major effect for child psychiatric disorders when genome-wide
association studies (GWAS) are performed.

If you wish to increase
your knowledge of
behavioural genetics
you may want to enrol in
the MOOC “Introduction
to Human Behavioral
Genetics” by Matt McGueof the University of
Minnesota. This course
entails committing 3-5hours/week during 8
weeks. Click on the image
to access the course (itrequires registration but it
is free).

The Rare Variant-Common Disease Hypothesis
This hypothesis holds that common psychiatric disorders are associated withan accumulation of rare mutations in a population. Proponents of this hypothesis
would postulate that one or several of these rare (less than 1% allele frequency)
mutations placed along the same critical developmental pathway may push
the organism towards having a child psychiatric condition (Hoffman & State,2010). This model has been used to help explain disorders in which there is theappearance of a new condition in an otherwise healthy family. This might occur
because, at times, the process of DNA replication and subsequent inheritance is
not perfect, leading to changes in the gene sequence that are passed from motheror father to child. This process of de novo mutation allows for new mutations to
be passed onto the child. In the rare-variant-common disease hypothesis, these denovo mutations become problematic when they accumulate. For example, theserare variants are overrepresented in autistic families where there is a single autistic
individual (so-called, “simplex” families) (Sebat et al, 2007). Because these are new
mutations that can then be passed along, they can have profound effects on eachsubsequent generation, making their concentration in the gene pool stronger. At

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5IACAPAP Textbook of Child and Adolescent Mental Healththeir extreme, rare variant mutations can act more like Mendelian traits which canthen be inherited if the individual reproduces.

The Gene-Environment Interaction Hypothesis
In this hypothesis, it is assumed that either common variants or rarevariants (most often the former) only have an effect on the expression of a childpsychiatric condition if placed into an environment in which those particulargenes were expressed and could therefore be deleterious. As noted below, thishypothesis has been quite central to plant genetics for some time, but really cameinto the human behavioral genetic literature with findings of Caspi and Moffitt
in the early 2000’s with a series of influential papers (Caspi et al, 2002; Caspiet al, 2003) proposing that the type of environment in which a child was raised
placed them at higher risk for later illness, depending on their genotype. Whilethese findings have had variable success in replication, they have provided thefoundation for the burgeoning field of epigenetics and gene expression in childand adolescent psychiatry.
In the following section, we will describe the types of genetics studies that
one is likely to encounter in the child and adolescent psychiatric literature and will
key them back to these three hypotheses.

DIFFERENT TYPES OF GENETIC STUDIES AND HOW
TO INTERPRET THEM
Here, we describe the types of genetic studies likely to appear in theliterature and provide some detail as to the questions that they are able to address.
Under the section “when is genetic testing appropriate” we provide information
about specific clinical genetic tests.

Family Studies
The most fundamental type of genetic study is the study of families. As
noted above, DNA is passed on from parent to child. Therefore, disorders inwhich genes are involved should run in families. Family studies have been usefulfor establishing the heritability of almost all child psychiatric conditions. Family
studies require information from at least two, but most often three or moremembers of the family, and analyses to determine whether a trait is more likely tooccur in certain families than in others. Of course, there is familial transmissionof more than DNA from parent to child. Wealth, for example, although it runs
in families, is not transmitted genetically. Both the environmental influences ofthe parents and their genes are responsible for familiality. In fact, in behavioral
genetics, it is assumed that a trait is influenced by at least three factors, the effects
of:•Genes (A),•The particular environment that affects an individual (E), and•The shared environment (C) – which is a measure of how two children
in the family are alike, regardless of their genetic similarity.

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EFFECT OF THE
ENVIRONMENTThe effect of the particularenvironment that influences
an individual (E term) inbehavioral genetic studies
also encompasses all of theerror of the models and notjust unique environmental
variance. In order to get abetter measure of uniqueenvironment, specifically,
one must turn to very
complicated designs suchas children of twins, which
are described well in
Boomsma et al (2002).

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IACAPAP Textbook of Child and Adolescent Mental Health

Figure A.13.2 Familiality of a trait includes both genetic and shared environmental components.

In family studies, one cannot separate out additive genetics (A) from sharedenvironment (C), because they both contribute to disorders running in families.
A limitation, therefore, of family studies is that, although they can establish
familiality, they cannot establish heritability, unless specific genetic markers aremeasured or environments are held constant (see Figure A.13.2). To separate
shared environmental from genetic associations within families, we need twin andadoption studies.

Twin and Adoption Studies
Twin and adoption studies can hold constant either environmental or
genetic factors, or both (in the case of twin-adoption studies). Adoption studies
are still relatively rare, but have provided marked insight into the environmental
factors that influence traits. In adoption studies, children are assessed to see
whether they are more similar to their birth parents or to their adoptive parents.
If the children resemble their adoptive parents more than expected by chance, thisindicates shared environmental influence. Adoption studies, while less common
than either twin or family studies, have demonstrated shared environmental
associations for antisocial behavior and personality, among others. The dearth ofadoption studies, however, likely reflects the difficulty of controlling for birthparent variables when researchers are unable to obtain information about one ormore birth parents (Alsobrook et al, 2002).
In contrast to adoption studies where the environment is varied, twin
studies allow systematic separation of the shared environment from additive
genetics based on the biological variance of twin type. Twins share either all of
their genes (identical or monozygotic twins) or half of their genes (fraternal or
dizygotic twins) allowing one to compare the concordance rate of a disorder
between monozygotic (MZ) twins and dizygotic (DZ) twins as a first test

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Click on the image toaccess a video clip about
what it is likely being an
identical twin (7:02)

7IACAPAP Textbook of Child and Adolescent Mental Health

QUANTIFYING HERITABILITY
Heritability can be defined as the proportion of phenotypic variance attributable to genetic variance. “Heritability is a statisticthat applies to population variance and not to individuals or to traits as a fixed feature. A high heritability means that genetic
factors account for much of the variation in the liability to show a particular trait in a particular population at a particular point
in time. It does not mean that genetic factors play a major role in the causation of that trait in any one individual’’ (Rutter et al,2006).
Heritability below 0.30 is considered low, between 0.30 and 0.60 moderate, and above 0.60 high. For example the heritabilityof intelligence is 0.45 to 0.75 (depending on age, higher as we become older) and up to 0.85 for bipolar disorder.
Heritability can be estimated by using twice the numerical difference of the MZ and DZ correlations. For example in a study ofobsessive-compulsive symptoms in children, the correlation between male MZ twins was 0.51 while the correlation between
male DZ twins was 0.34, leading to heritability estimate of 0.34 [2(rMZ-rDZ)=2(.51-.34)] (Hudziak et al, 2004). Often, as in thisexample, the MZ concordance rate is somewhere between the DZ twin concordance rate and twice the DZ twin concordance
rate. In this situation, both additive genetics and shared environment are involved. To estimate the contribution of each, twin
researchers use structural equation modeling, which assumes that additive genetics and shared environment are unmeasured,or latent, variables and imputes the relations between them based on the data (for a review see Rijsdijk & Sham, 2002)
Estimates of heritabilities of common child psychiatric disorders are discussed below and are provided in Table A.13.1.

for genetic contributions. If a disorder is almost entirely related to genes, theconcordance rate between MZ twins will be twice that of DZ twins, because MZ
twins share 100% of their DNA sequence while DZ twins share, on average, only
50%—this assumes that the genetics are additive, without evidence of genetic
dominance, rater bias, or other interaction. On the other hand, if genes are not
involved at all, the MZ and DZ twin concordance rates will be equal.
The role of estimating additive genetic effects using twin designs is mostconsistent with the common variant-common disease model listed above whereby
all of the genetic effects across the population of twins are modeled together.
Twin studies have the additional advantage of being able to control for genetic
effects while testing specific environmental effects by comparing MZ twins whoare concordant and discordant on a particular trait. In this situation, de novo
mutations may play a larger role, as it is possible for one MZ twin to carry amutation while the other does not (Ehli et al, 2012); supporting the rare variantcommon disorder hypothesis. However, this is rare for highly heritable disorders.
Twin studies can also be used to evaluate more complicated questions such as
issues of gender effects (using opposite sex twins) and questions of informant bias.
For other advantages of twin designs, see Boomsma et al (2002).

Candidate Gene Studies
Once family studies have determined familiality and twin or adoption
studies have determined heritability, researchers can then investigate which genes,
exactly, are involved. Uncovering the genes that are involved should enable us todesign and test treatments that are specific to particular physiological pathways
involved in particular phenotypes. Studies are often conducted on candidate genes– that is to say, genes hypothesized to be involved in a phenotype for some reason.
A classic example is the dopamine receptor D4 (DRD4) gene which, as the nameimplies, encodes the D4 subtype of the dopamine receptor. The DRD4 genehas multiple single nucleotide polymorphisms (SNPs) associated with it and also
has a site containing a variable number of tandem repeats (VNTR). This VNTR,
the 7-repeat sequence of the DRD4 gene, has been used frequently as a marker

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SNPs
A single nucleotide
polymorphism, or SNP(pronounced like “snip”),
is a difference in a single
nucleotide along the DNA
sequence. Because SNPs
vary between people,
they can be used as asource of variation along
the genome. Thus far, itappears that there areabout 10 million SNPs
spaced along the humangenome. Researchers
use these SNPs to “tag”
portions of the genome.
When a SNP is within agene, variation in that SNP
may be a marker that can
associate that gene withdisease. When they areoutside of a gene, they areoften still correlated withfunctions of genes throughlinkage disequilibrium,
which is a term that refers
to how likely two markers
are to be inherited witheach other. Sometimes
SNPs will be said to be inhigh linkage disequilibrium(high LD), meaning that
they, for the most part, canbe substituted one for theother because they arecorrelated very highly.

8IACAPAP Textbook of Child and Adolescent Mental Healthfor attention-deficit/hyperactivity disorder (ADHD). Investigators first started
examining the dopamine genes, however, because of the dopamine hypothesis of
ADHD which, essentially, arose from the clinical finding that medications used
for the treatment of ADHD (i.e., the psychostimulants) have dopamine re-uptake
inhibition as one of their mechanisms of action. Dopamine receptor genes were,
therefore, explored as candidates and were found to be associated with ADHD.
Another way of developing candidates is to use pedigrees with known genetic
changes to identify gene regions which may be involved. A final pathway to a
candidate gene is to examine the results of either linkage or genome-wide association
studies (GWAS, described below) and to choose likely “hits”.
Unfortunately, candidate gene studies fall prey to a number of difficulties.
Foremost has been the lack of replication across studies. Many highly significant
findings in one population have not been replicated in others. Some of this may be
due to the relative distribution of risk alleles within particular populations – that
is, allele frequencies vary by race and by geographical region. This feature of SNPs
can lead to population stratification – association of an allele with a disorder only
because both the allele and the disorder are more common in a subpopulation.
Moreover, because only one SNP is typically tested at a time, there is a higher
prior probability of it being detected than if the whole genome was being tested.
Many candidate gene tests do not survive correction for comparisons across theentire genome. Consequently, many researchers prefer to test only candidate SNPs
that have been derived from a whole-genome approach such as linkage or GWAS
studies.

Linkage Studies
Linkage studies were the first type of molecular genetics study that wasable to search across the entire genome and determine where on the chromosome
a disease locus might lie. In linkage studies, at least 2 members of a pedigree,
preferably three or more, are examined to see whether portions of the genome cosegregate with a disorder. Critical to linkage is the idea of identity by descent – thatis, the matching of specific chunks of DNA that are inherited together along with adisorder. By examining the distance between these chunks of DNA, the likelihoodof recombination given a particular distance of markers from one another, and the
proposed genetic relations among members of a family, whole genome scans canbe conducted on relatively small sample sizes with smaller numbers of markers
than needed for genome-wide association studies. A disadvantage to linkage
studies is that the spatial resolution on the chromosome is not very high, so thata linkage peak, which would denote an important association with a phenotype,may contain many genes underneath it. Still, linkage has been a critical tool for
detecting candidate genes for further study.

MOLECULARGENETICS
The branch of genetics that
deals with the structure andactivity of genetic material
at the molecular level.

VARIABLE NUMBER
OF TANDEM
REPEATS (VNTRs)
VNTRs are parts of the
genome where there aresegments of DNA that are
repeated. These segments
can vary between
individuals, making
them markers of genetic
variability.

Genome-Wide Association Studies (GWAS)
Linkage studies have fallen a bit out of vogue with the advent of relatively
inexpensive chip-based technologies that sample across thousands or millions ofcommon SNPs at once. GWAS can tag these common SNPs across the genome
and can simultaneously perform millions of association tests with the disorder
being studied. Because statistical controls take account of multiple comparisons

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CO-SEGREGATION
The tendency for closely
linked genes and genetic
markers to be inherited
together.

9IACAPAP Textbook of Child and Adolescent Mental Healthacross the genome, large samples are needed to obtain enough power to detectassociations. Even with large samples and stringent statistical controls, GWAS hits
have been difficult to replicate. For example, childhood ADHD has been shownto have additive genetic factors accounting for up to 70% of the variance in twin
studies, but a recent meta-analysis using over 1.2 million SNPs and nearly 10,000
individuals found no genetic hits (Neale et al, 2010). That said, other highly
heritable traits such as height, weight, and diabetes, despite having more easily
defined phenotypes, have required even bigger samples to find associated genes
in GWAS. Failure to find genes of major effect using GWAS is consistent withthe common disorder-common variant hypothesis, but because rare variants are
excluded from GWAS, such findings do not necessarily contradict the rare variant
hypothesis. When copy number variations (which are a collection of catalogued
rare variants that can be included on microarray chips) are included in wholegenome studies, for example, rare variant findings have emerged for ADHD,
autism, and other disorders.

Genome-Wide Complex Trait Analysis (GCTA)
An alternative way to use whole genome data has been to examine theadditive effects of genes directly. Genome-wide complex trait analysis, a relatively
new method, essentially takes large samples and creates a genetic similarity matrix
of correlations among the alleles from all measured SNPs among all individuals.
By using the degree of measured genetic similarity between individuals andcomparing it to the likelihood of trait expression, researchers can examine directly
the heritability of a particular child psychiatric condition. GCTA requires larger
sample sizes than traditional twin methods (~3000), and a recent comparisonof the GCTA heritability estimates to twin heritability estimates for childhood
disorders showed lower estimates in GCTA than in the traditional twin models(Trzaskowski et al, 2013). Still, the ability to examine heritability directly through
GCTA (or other methods being developed) without the need for sampling of
twins is an exciting development. GCTA studies are built upon and strongly
support the common disorder-common variant hypothesis.

Epigenetics
Epigenetics provides an additional approach to psychiatric genetics. Literally
meaning “outside of genetics”, epigenetics was first used to describe heritablechanges in the genome that are not related to changes in the DNA sequence.
These changes could include changes in DNA methylation (wherein a methylgroup [CH3] is placed on a cytosine-guanine base pairing changing the function of
the gene) or histone deacetylation (wherein an acetyl group [COCH3] is removed
from histone complexes), changing DNA expression. However, epigenetics hascome to mean any change in the genome that does not alter DNA structure but
can alter gene expression. As noted above, examination of DNA sequences allows
the uncovering of variance in the alleles that may affect proteins. Proteins, as
noted above, do the work of the cell. Thus, changes in gene expression are likely to
be associated with altered neuronal function, regardless of the allele sitting on thechromosome. However, a challenge for epigenetics is that, unlike gene structure,
which is the same regardless of the cell being examined, gene expression changes
by cell type. Thus, the expression of a particular gene in the buccal mucosa or a

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EPIGENETICS
This term refers toheritable changes in gene
expression that do not
involve changes to theunderlying DNA sequence;a change in phenotype
without a change in
genotype. In other words,
it refers to cellular andphysiological phenotypic
trait variations that arecaused by external orenvironmental factors thatswitch genes on and off
and affect how cells readgenes, instead of variations
caused by changes in the
DNA sequence.

10

IACAPAP Textbook of Child and Adolescent Mental Healthperipheral lymphocyte might not represent the expression of that gene in the brain
area of interest for a child psychiatric phenotype. There is some evidence, however,that there may be enough of a signal in peripheral tissue to allow epigenetics
outside of the brain to be useful for child psychiatric conditions. This is an areaof active research and, despite this limitation, epigenetics is a burgeoning field
because the idea of altering gene expression rather than DNA structure offers atantalizing explanation for how genes and environments might interact. To learn
more about this, please watch the excellent and entertaining talk about What Is
Epigenetics? by Nessa Carey.

Gene x Environment (GxE) Interplay
I use the term gene x environment interplay because genetic effects are notjust moderated by environments but can also correlate with them directly. For
example, there can be GxE correlations whereby the expression of a particular
genetic trait makes it more likely that one will enter a particular environment
which, in turn, makes the expression of the phenotype even more likely. TheseGxE correlations are probably more common in families than we appreciate.

Click on the figure tohear a very entertaining
talk about “What Is
Epigenetics?” By Nessa
Carey, author of “Junk
DNA” (29:25).

It has long been known that genes and the environment interact with one
another. In some ways, GxE interactions are the foundation of natural selection.
Organisms whose genotypic expression allows them to survive in the environment
in which they were placed will be able to reproduce, passing on their genes to thenext generation. Elmer Heyne, the great plant geneticist, knew this well as heattempted to develop strains of wheat. He recognized that what is inherited is themanner of reaction to a given environment – with certain strains of wheat able
to adap to wet environments and others to arid environments. It is this concept– that a particular allele is not good or bad or advantageous or high risk, but rather
that an allele can be any of these depending on the environment – that lays thefoundation for GxE studies.
The field of psychiatric genetics became enamored with the idea of finding
specific causal alleles. When these were not easily uncovered, some researchers
turned to the study of the environment as a moderator of the effects of particularrisk alleles. As an example, research by Caspi, Moffitt, and their colleagues showedthat an allele of the neurotransmitter-metabolizing enzyme monoamine oxidase A(MAOA) gene increased the risk for adult antisocial behavior among individuals
who had experienced childhood adversity (Caspi et al, 2002). Similarly, they
showed that an allele of the serotonin transporter gene (5HTTLPR) increased therisk for adult depression among individuals who had been maltreated in childhood(Caspi et al, 2003). Although meta-analyses have cast doubt on the effect sizes, theconcept of GxE interaction has remained at the forefront of psychiatric genetics
over the past 10 years. In fact, at this stage the old question of nature versus nurturehas really been answered. It is, almost always, nature and nurture working towards
the expression of child mental health phenotypes.

CHILD AND ADOLESCENT PSYCHIATRICCONDITIONS KNOWN TO BE INHERITED
Nearly all of the common child and adolescent psychiatric conditionsor their related constructs have been found to have genetic components. While
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11IACAPAP Textbook of Child and Adolescent Mental Health

Table A.13.1 The heritability of common child psychiatric conditions
based on twin, family, and adoption studies.
DISORDER

HERITABILITY

REFERENCE

Autism spectrum disorder60-90%

Posthuma & Polderman(2013)

ADHD~70%

Posthuma & Polderman( 2013)

Anxiety

20-40%

Smoller et al (2009)

Conduct disorder39-63%

Bornovalova et al (2010)Childhood depression

16-43%

Rice et al (2002)

DMDD/irritability/
dysregulation

63-75%

Boomsma et al (2006)

Learning disorders

58-65%

Willcutt et al (2010)

Oppositional defiant
disorder21-57%

Hudziak et al (2005)

Obsessive-compulsive
disorders

39-41%

Taylor et al (2011)

Tourette syndrome~77%

Mataix-Cols et al (2015)

it may seem strange to make such an absolute statement, there is not a single
DSM-5 condition listed in the childhood disorders section where heritability has
been tested that has not had a demonstrable genetic component. The relevanceof related constructs is illustrated by the new DSM-5 category of disruptive
mood dysregulation disorder —which has not been tested in a twin or GCTA
design— but the constructs of irritability and of dysregulation, both related tothe disruptive mood dysregulation construct, have both been demonstrated to be
heritable. Table A.13.1 lists the estimated heritability for many of the commonchildhood psychopathologies.
The estimates in Table A.13.1 come from studies of twins and families.
But, because of the advances in genome-wide complex trait analysis and otherdirect measurement approaches to heritability, these may need to be revised soon.
In general, when genome-wide complex trait analysis is applied to twin samples,
heritabilities tend to be lower in GCTA than when using the twin methodology.
Whether genome-wide complex trait analysis underestimates or twin models
overestimate heritability is an area of active research.

Known Genetic Conditions of Importance to Mental HealthProfessionals
Keeping in mind that many of the common child and adolescent
psychiatric disorders involve complex traits with polygenic inheritance, some
genetic conditions are known to have psychiatric symptoms as part of theirpresentation (Siegel & Smith, 2011). These conditions may present to childand adolescent mental health professionals for behavioral management or forevaluation of associated developmental delays. In these cases, an understanding of

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12IACAPAP Textbook of Child and Adolescent Mental Healththe general presentation of children with these conditions is also important. A few
examples are provided below. More details can be found on the Genetics Home
Reference page of the US National Institute of Health.

Down syndrome
This describes a constellation of symptoms associated with three copies(trisomy) of chromosome 21. Trisomy 21 is often detected during prenatal
screening and has been associated with both advanced maternal and paternalage. Trisomy 21 occurs in about 1 in 1000 live births. Parents most often haveunremarkable karyotypes and the trisomy is considered a de novo change. It
can also occur as a partial trisomy wherein just a portion of chromosome 21 istransmitted – most frequently due to Robertsonian translocation. The additional
genetic material from the extra chromosome results in overexpression of a numberof genes, likely leading to the cognitive phenotype (see also Chapter C.1).
Non-psychiatric clinical characteristics: Down syndrome has distinguishingfacial features (up-slanting palpebral fissures, epicanthal folds, a broad nasal bridge,
small mouth, relatively large tongue), posteriorly rotated ears, short stature, andsingle palmar crease. There can be associated cardiac problems (e.g., ventricularseptal defect), gastrointestinal problems (such as Hirschsprung’s disease, duodenalatresia, or celiac disease), and other nonpsychiatric medical problems.

ROBERTSONIAN
TRANSLOCATIONA Robertsoniantranslocation is when aportion of an acrocentricchromosome (achromosome with onevery short arm and one
long arm) is rearranged
with portions of anotheracrocentric chromosome.
Because chromosome
21 is acrocentric, its
long arm rarely, but
occasionally, rearranges
with chromosomes 14 or
15, creating an unbalanced
amount of chromosome
21 material in the offspringleading to Down syndrome.

Psychiatric clinical characteristics: Most individuals with trisomy 21 havesome form of intellectual disability. Language delay is common. While social
responsiveness is not necessarily impaired, up to 10% of individuals with trisomy
21 meet the criteria for an autism spectrum disorder. Patients are at increased
risk for many child psychiatric disorders and neurological problems including
ADHD, anxiety, depression, seizures, and, later in life, dementia.
Diagnosis: Karyotype.

Fragile X syndrome
In contrast to Trisomy 21, which typically occurs as a de novo mutationin the germ line cells of a parent, fragile X syndrome is inherited from parent tochild. This makes it the most common inherited condition leading to intellectual
disability, occurring at a rate of about 1 in 4000 live male births and 1 in 8000
live female births. As noted above, the pathogenesis of fragile X syndrome
involves increasing numbers of trinucleotide repeats – specifically cytosineguanine-guanine (or CGG) repeats in the FMR1 gene on the X chromosome.
Across generations, more repeats accumulate. When they accumulate higher thanabout 200 repeats, the clinical syndrome emerges. Because one X chromosome isinactivated in the cells of females, they tend to be less affected than males. This
process of X-inactivation allows for the dosing of genes on the X-chromosome
between males and females to be essentially the same. Through an epigenetic
process, cells in females express only one of their two X-chromosomes. In the caseof X-linked disorders, the affected chromosome is usually inactivated. It can still,
however, be transmitted to offspring through the maternal line. Males who receive
the affected X chromosome, however, have the affected FMR1 gene unopposed byanother X chromosome (see also Chapter C.1).

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FLUORESCENCEIN SITUHYBRIDIZATION(FISH)
A technique whereby
particular parts of the
genome are tagged witha fluorescent marker andchanges to DNA structure
can be identified.

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IACAPAP Textbook of Child and Adolescent Mental Health

Non-psychiatric clinical characteristics: Classical features may take until
puberty to be manifest but consist of macrocephaly, prominent ears, a long,narrow face and macro-orchidism (in males). There is frequent hyperextendabilityof joints such as in the fingers.
Psychiatric clinical characteristics: Males most often demonstrate somedevelopmental delay – often with intellectual disability that correlates roughlywith the number of CGG repeats present. Attention, communication, and social
pragmatics are often impaired – even in mildly affected females. Autistic features
are common with around 1/3 meeting criteria for an autism spectrum disorder.
Other emotional and behavioral problems also occur.
Diagnosis: Fluorescence in situ hybridization (FISH) testing for fragile X.

Williams syndrome
Occurring in about 1 in 10,000 live births, Williams syndrome is related
to a deletion in a region on chromosome 7 affecting around 30 genes involved indevelopment, cardiovascular disease, and connective tissue development.
Non-psychiatric clinical characteristics: Children with Williams syndrome
have characteristic facial features: a broad forehead, a wide mouth with full lips,
full cheeks, and a narrowing of the distance between the temples. There may bejoint problems and increased elasticity of the skin and joints. Depending on theextent of the deletion, there can be supravalvular aortic stenosis of the heart.
Psychiatric clinical characteristics: There is typically mild to moderateintellectual disability, especially visual-spatial difficulties. Auditory rotememorization and language may be spared. They may have a superficial hypersocial
personality but may miss subtle social cues. ADHD symptoms are common, as
are anxiety disorders and sleep disturbance.
Diagnosis: FISH testing or microarray.

Prader-Willi syndrome
Prader-Willi syndrome is one of two conditions that are associated withdeletion of chromosome 15q11-q13. Prader-Willi syndrome most frequently
occurs when the child’s paternal copy of this gene is deleted and the maternal
copy is inactivated. Alternatively, the child could have received two copies ofthe maternal chromosome 15 (so-called uniparental disomy) or there could havebeen some other de novo mutation that inactivates the genes. In all, Prader-Willi
syndrome occurs in about 1 in 15,000 live births.
Non-psychiatric clinical characteristics: The earliest manifestations appear in
infancy with poor feeding, slow growth, developmental delay, and hypotonia. In
childhood, hyperphagia becomes common with resultant obesity and later diabetes.
There are characteristic facial features with a narrow forehead, triangular mouth,
and almond-shaped eyes. Growth delay, particularly with small, narrow hands andfeet, are common. Pubertal development is often delayed and individuals haveunderdeveloped genitalia.
Psychiatric clinical characteristics: Mild to moderate intellectual disability iscommon but not universal. Most of the manifestations of Prader-Willi are related
to compulsive behavior. Most prominent is hyperphagia or compulsive eating, but

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PCR
PCR or polymerase chain
reaction, is a molecular
genetics technique used
to amplify a region of DNA
which can then be used in
testing.

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IACAPAP Textbook of Child and Adolescent Mental Healthskin picking, nose picking, and hair pulling are not uncommon. Obsessions do
not often occur with the compulsions. Hoarding and gorging of food frequently
occurs, as does poor frustration tolerance when limits are placed on eating.
Emotion regulation difficulties may continue into adolescence and adulthood.
Diagnosis: Methylation PCR.

Angelman syndrome
The mirror of Prader-Willi syndrome is Angelman syndrome, which affects
around 1 in 15,000 live births as well. In this case, there is loss of the maternal copyof the UBE3A gene on chromosome 15 due to a deletion with the maternal copyof the gene, two copies of the paternal allele or other mutations being inherited.
Non-psychiatric clinical characteristics: Seizures emerging in the first 2 yearsof life are not uncommon. There may be some hypopigmentation of the skin andhair and coarse facial features as individuals age.
Psychiatric clinical characteristics: The earliest manifestations are delayeddevelopment and intellectual disability. Children with Angelman syndrome
appear happy and tend to laugh readily and frequently, at times associated withhand flapping. There is social disinhibition. Sleep is frequently poor.
Diagnosis: Methylation PCR and/or UBE3A specific mutation analysis.

Rett syndrome
Resulting from a mutation in the MECP2 gene, Rett syndrome occurs
almost exclusively in girls at a rate of about 1 in 8,500 live female births. The
MECP2 gene sits on the Xq28 locus and is X-linked dominant. Most males withthe mutation die in pregnancy or infancy.
Non-psychiatric clinical characteristics: Classically, this syndrome ischaracterized by mildly delayed or typical early development for the first 6-18
months followed by profound developmental delay, autistic traits, and thecharacteristic loss of purposeful hand movements. These hand movements are
replaced with hand wringing, washing, or clapping movements. Unfortunately,
there is eventual loss of most motor function. Seizures are very common.

Click on the figure to hear
Robert Plomin from theInstitute of Psychiatry(King’s College, London)
discuss some of the social
issues brought about
by behavioral genetics(45:15)

Psychiatric clinical characteristics: The earliest manifestations aredevelopmental delay beginning around 6-18 months which frequently resultsin little or no language. Along with hand movements, sleep difficulties can bepresent, as can irritability and autistic-like behaviors.
Diagnosis: MECP2 gene sequencing.

22q11.2 deletion syndrome
The 22q11.2 deletion occurs relatively frequently—rates estimated as 1 in
4,000 people—which may be an underestimate because of the variability in thepresentation of the syndrome. The loss of the TBX1 gene in this region may
be responsible for many of the nonpsychiatric characteristics, while loss of the
COMT gene, which codes for a protein involved in catecholamine metabolism,
may be responsible for the psychiatric symptoms.
Non-psychiatric clinical characteristics: These are highly variable, including

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15

IACAPAP Textbook of Child and Adolescent Mental Healthcleft lip and palate, other midline structural defects, ventricular septal defect,
small or absent thymus gland, low calcium levels, and the conotruncal anomaly face
syndrome consisting of hypertelorism, small, upward slanting palpebral fissures,prominent eyelids, a low nasal bridge and a small mouth.
Psychiatric clinical characteristics: They are highly variable. There may beborderline or mild intellectual disability. Attention problems, anxiety, or social
withdrawal can be present at a young age. Many children meet the criteria foran autism spectrum disorder. Psychotic disorders are over-represented in thesechildren.
Diagnosis: FISH testing for 22q11 deletion.

OthersThere are other syndromes of which one needs to be aware also. Amongothers these include Turner syndrome – a single X chromosome with no paired
X or Y, responsible for short stature and possibly intellectual disability; SmithMagenis syndrome – associated with loss of the RAI1 gene on chromosome 17
and is associated with sleep disturbance, short stature, temper tantrums, selfhugging, finger-licking, and self-injury; deletion or duplication of 16p11 which
may predispose to autism, epilepsy, schizophrenia, and intellectual disability;

WHEN IS GENETIC TESTING APPROPRIATE?
A frequently asked question is: “Knowing what we know now about
psychiatric genetics, is there a role for genetic testing for the common disorders?”
In general, for most of the common child psychiatric conditions, there is no
current role for genetic testing. Despite a proliferation of for-profit companies
that test cheek swabs or salivary samples and provide genotyping results, thescience of prediction for common genetic markers is not yet helpful to mental
health professionals. In fact, it seems absurd to pay high fees for information
about nonspecific genetic markers that may increase or decrease risk by 1%. It
is especially silly to pay such fees when much better information can be gleaned
from empirically-based clinical assessment of patients and documentation of theirfamily history. Genetic testing is nevertheless indicated when two or more of thefollowing conditions exist:•

Multiple congenital system involvement (e.g., cardiac, pulmonary,gastrointestinal)•

Presence of intellectual disability•

Presence of unusual or abnormal facies•

Multiple affected individuals in a family.

In general there is no
current role for genetic
testing for most of thecommon child psychiatricconditions.

In general there is no current role for genetic testing for most of thecommon child psychiatric conditions.
It was previously recommended that patient karyotyping and perhaps
FISH testing be done in these situations (Tsuang et al, 2000). However, after theserecommendations were made and many other guidelines came out, there havebeen significant advances in genetic technologies. At this point, for intellectual
disability, autism spectrum disorders, or multiple congenital involvement the

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IACAPAP Textbook of Child and Adolescent Mental Healthrecommendation is to start with a chromosomal microarray assay rather thana standard or high resolution karyotype (Miller et al, 2010). If an abnormality
is detected, it should be followed up by confirmation and the parents shouldbe tested. If there are no chromosomal microarray abnormalities, but clinicalfindings suggest a genetic disorder, then more specific tests (e.g., single gene tests,
FISH for fragile X, or methylation studies) can be performed. However, eventhe microarray technologies may soon be superseded by next-generation DNA
sequencing technologies, which literally map every base-pairing in the genome (orthe exome) of an individual.

GENETIC COUNSELING IN MENTAL HEALTHSERVICES

MAPPING THE
EXOMEThis process would map
the part of the DNA that
contains the sequencesthat remain within mature
RNA after a process, calledsplicing, removes partsof the RNA called introns.
Exomes are thought tobe most likely related toprotein coding regions.

An awareness of genetic contributions to psychiatric symptoms canhave important implications for diagnosis and patient care (Finn & Smoller,
2006). When genetic counseling becomes relevant, the following points should
be considered: Firstly, counseling begins with an accurate diagnosis. A careful
history and physically examining the clinical characteristics of known conditions
may point towards a particular diagnosis, which can then be used to educate
families prior to genetic counseling. The education of individuals and families,
be it broadly about genetic concepts or specifically about a suspected genetic
syndrome, starts with the mental health professional or the primary care clinician.
The primary care clinician should be consulted so that all testing and counseling iscoordinated. Next, a genetics consultation can be offered prior to ordering testing.
The referring clinician should inform the family that the yield of this kind ofevaluation, especially in cases of autism and developmental delay, is likely to below. After that, the evaluation should be tiered, in that the highest yield tests
should be considered first.
Genetic counseling should be provided as a part of the clinical genetics
consultation and would include confirming the diagnosis, obtaining a family
history, evaluating the intellectual and emotional capacity of family members,
evaluating the burdens and benefits of testing, and forming a tiered plan (Schaefer& Mendelsohn, 2013; Finn & Smoller, 2006). Recurrence risks (i.e., the likelihoodof another offspring having the same disorder) should be discussed. Nondirective
counseling should be made available to facilitate decision making about options
for dealing with recurrence. Genetic counseling may be helpful to those whorequest it, but there is very little empirical evidence regarding who should receive
such counseling, when they should receive it, and who should provide it. Thereis a clear need for systematic research in this area with suggestive findings that
support the requirement for an increased knowledge base in genetic testing (Finn& Smoller, 2006).

CONCLUSION
We have described the state of psychiatric genetics for child andadolescent mental health professionals. The central concept is that heritable traits
passed on from parent to child interact with the child’s environment to shapedevelopmental psychopathology. While most common child and adolescent

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Due to its growing
importance, child andadolescent mental healthprofessionals need to
be increasingly awareof genetic issues tounderstand the relevanceof research findings, tobe able to explain theseconcepts to patientsand their families and,occasionally, to refer themfor genetic counseling.
Changes in genetic
technology, science, andrecommendations are
occurring at a rapid rate,
which will accelerate
further as new technologies
become cheaper and morecommonplace.

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IACAPAP Textbook of Child and Adolescent Mental Healthmental health conditions are likely polygenic and caused by the additive effects ofmultiple genes increasing risk, rare variants and single gene effects are associatedwith certain conditions. Many of these single gene (or single chromosomal region)
disorders are listed above along with their psychiatric and nonpsychiatric clinicalcharacteristics. Environments may operate on genes by turning them off and on
via epigenetic processes. Child and adolescent mental health professionals mayneed to explain these concepts to patients and their families and, occasionally,
may need to refer them for genetic counseling. Changes in genetic technology,
science, and recommendations are occurring at a rapid rate, which may accelerate
further as next generation sequencing technologies become cheaper and morecommonplace.

•

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Jean-Baptiste Lamarck(1774-1829 ), a French
biologist, developed atheory of evolution which
included the idea that
traits can be acquired
and then passed along
to offspring. During hislife Lamarck’s ideas did
not receive much supportand scientific attention but
have raised more interest
recently. Forms of “soft”
or epigenetic inheritancewithin organisms havebeen suggested as neoLamarckian in nature.
“Lamarck is far fromdead ... The inheritance ofacquired characteristics
is one of those ideasthat holds out eternalfascination. It seems soright. If only inheritancewere Lamarckian, evolution
would be orderly, andefficient”(Hull DL (1984). Lamarck among
the Anglos. Introduction toLamark’s Zoological Philosophy.
University of Chicago Press).

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IACAPAP Textbook of Child and Adolescent Mental Health

REFERENCES
Alsobrook JP, Grigorenko E, Pauls DL (2002). Genetic
influences on child psychiatric conditions. In: Lewis M(ed) Child and Adolescent Psychiatry: A Comprehensive
Textbook 3rd ed. Philadelphia, PA: Lippincott Williams& Wilkins
Boomsma D, Busjahn A, Peltonen L (2002). Classical twin
studies and beyond. Nature Reviews Genetics, 3:872882
Boomsma DI, Rebollo I, Derks EM et al (2006). Longitudinalstability of the CBCL-juvenile bipolar disorderphenotype: A study in Dutch twins. BiologicalPsychiatry, 60:912-920
Bornovalova MA, Hicks BM, Iacono WG et al (2010). Familialtransmission and heritability of childhood disruptive
disorders. Amercan Journal of Psychiatry, 167:10661074
Caspi A, Mcclay J, Moffitt TE et al (2002). Role of genotype in
the cycle of violence in maltreated children. Science,
297:851-854
Caspi A, Sugden K, Moffitt TE et al (2003). Influence of life
stress on depression: Moderation by a polymorphismin the 5-htt gene. Science, 301:386-389
Constantino JN, Zhang Y, Frazier T et al (2010). Siblingrecurrence and the genetic epidemiology of autism.
American Journal of Psychiatry, 167:1349-1356
Ehli EA, Abdellaoui A, Hu YS et al (2012). De novo andinherited CNVs in MZ twin pairs selected for
discordance and concordance on attention problems.
European Journal of Human Genetics, 20:1037-1043
Finn CT, Smoller JW (2006). Genetic counseling in psychiatry.
Harvard Review of Psychiatry, 14:109-121
Hoffman EJ, State MW (2010). Progress in cytogenetics:
implications for child psychopathology. Journal of theAmerican Academy of Child and Adolescent Psychiatry,
49:736-751
Hudziak JJ, Derks EM, Althoff RR et al (2005). The genetic andenvironmental contributions to oppositional defiant
behavior: A multi-informant twin study. Journal of theAmerican Academy of Child and Adolescent Psychiatry,
44:907-914.
Hudziak JJ, Van Beijsterveldt CE, Althoff RR et al (2004).
Genetic and environmental contributions to the Child
Behavior Checklist Obsessive-Compulsive Scale: across-cultural twin study. Archives of General Psychiatry,
61:608-616
Mataix-Cols D, Isomura K, Perez-Vigil A et al (2015). Familial
risks of Tourette syndrome and chronic tic disorders.
A population-based cohort study. JAMA Psychiatry,
72:787-793
Miller DT, Adam MP, Aradhya S et al (2010). Consensus
statement: Chromosomal microarray is a firsttier clinical diagnostic test for individuals with

Genetics

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developmental disabilities or congenital anomalies.
American Journal of Human Genetics, 86:749-764
Neale BM, Medland SE, Ripke S et al (2010). Meta-analysis of
genome-wide association studies of attention-deficit/
hyperactivity disorder. Journal of the American Academyof Child and Adolescent Psychiatry, 49:884-897
Posthuma D, Polderman TJ (2013). What have we learned
from recent twin studies about the etiology ofneurodevelopmental disorders? Current Opinion in
Neurology, 26:111-121
Rice F, Harold G, Thapar A (2002). The genetic aetiology ofchildhood depression: A review. Journal of Child
Psychology and Psychiatry, 43:65-79
Rijsdijk FV, Sham PC (2002). Analytic approaches to twin datausing structural equation models. Brief Bioinformatics,
3:119-133
Rutter M, Moffitt TE, Caspi A 2006. Gene-environment
interplay and psychopathology: Multiple varieties but
real effects. Journal of Child Psychology and Psychiatry,
47:226-261.
Schaefer GB, Mendelsohn NJ (2013). Clinical genetics
evaluation in identifying the etiology of autism
spectrum disorders: 2013 guideline revisions. Genetic
Medicine, 15:399-407
Sebat J, Lakshmi B, Malhotra D et al (2007). Strong associationof de novo copy number mutations with autism.
Science, 316:445-449
Siegel MS, Smith W E (2011). Psychiatric features in children
with genetic syndromes: Toward functional
phenotypes. Pediatric Clinics of North America,
58:833-864
Smoller JW, Block SR, Young MM (2009). Genetics of anxiety
disorders: The complex road from DSM to DNA.
Depression and Anxiety, 26:965-975
Taylor S, Asmundson GJ, Jang KL (2011). Etiology of obsessivecompulsive symptoms and obsessive-compulsive
personality traits: Common genes, mostly different
environments. Depression and Anxiety, 28:863-869
Trzaskowski M, Dale PS, Plomin R (2013). No genetic influence
for childhood behavior problems from DNA analysis.
Journal of the American Academy of Child andAdolescent Psychiatry, 52:1048-1056.
Tsuang D, Faraone SV, Tsuang MT (2000). Psychiatricgenetic counseling In: Bloom FE, Kupfer DJE (eds)
Psychopharmacology-4th Generation of Progress. New
York, NY: Raven Press
Willcutt EG, Pennington BF, Duncan L et al (2010).
Understanding the complex etiologies ofdevelopmental disorders: Behavioral and molecular
genetic approaches. Journal of Developmental and
Behavioral Pediatrics, 31:533-544

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IACAPAP Textbook of Child and Adolescent Mental HealthAppendix A.13.1
SELF-DIRECTED LEARNING EXERCISES AND SELF-ASSESSMENT
MCQ A.13.1 Most child and adolescent
psychiatric disorders are:

MCQ A.13.5
through:

Heritability is stablished

A. Not inherited

A. Family studies

B. Inherited following a Mendelianmodel

B. Twin and adoption studies

C. Inherited single-gene disorders
D. Inherited but involve multiple genes
E. Due to de novo mutations
MCQ A.13.2 A strand of DNA in achromosome is called:

A. Chromatid

C. Candidate gene studies
D. Linkage studies
E. Genome-wide association studies
MCQ A.13.6

Co-segregation is:

A. The additive effect of damaged
genes

B. Allele

B. When segments of DNA are repeated

C. Centromere

C. The effect of environmental influences on gene expression

D. Nucleotide
E. BaseMCQ A.13.3 A gene located in the short armof chromosome 7, region 3, band 1, sub-band
2 would be annotated as:

A. 7q31.2
B. 3p71.2

D. The tendency for closely linked
genes to be inherited together
E. The tendency for a single nucleotide polymorphism (SNP) to find amatch
MCQ A.13.7
by a:Fragile X syndrome is caused

C. 2p31.7

A. Trisomy of chromosome X

D. 7p31.2

B. Deletion of chromosome 15

E. 1q2.3.7

C. Deletion in a region on chromosome 7

MCQ A.13.4 The number and appearanceof chromosomes in the nucleus of a cell iscalled:A. Phenotype

D. Single X chromosome with nopaired X or Y
E. Abnormal number of trinucleotide
repeats on the X chromosome

B. Alleles
C. Genome
D. Exome
E. Karyotype

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IACAPAP Textbook of Child and Adolescent Mental Health

MCQ A.13.8

Genetic testing:

A. Is advisable in the case of children
with ADHD

MCQ A.13.11 The central dogma of biology
states that:

A. All living beings are made of cells

B. Helps to choose the right treatment
for a specific child

B. DNA is only contained in the nucleus of cells

C. Is not advisable for most commonchild psychiatric conditions

C. RNA -> DNA -> protein

D. In most cases will ease parents
anxiety

E. DNA is a double helix

E. Is easily available in most countries
nowadays
MCQ A.13.9 Prader-Willi Syndrome andAngelman syndrome have in common that
both:

A. Preferentially affect females
B. Involve deletion of sections of chromosome 15
C. Involve hoarding of food

D. DNA -> RNA -> protein

MCQ A.13.12 Epigenetics refers to:

A. Changes in the organism that areoutside of cells
B. Evolution due to natural selection
C. Changes in RNA protein binding
D. Heritable changes that do not involve changes in DNA sequence
E. The field of study that encompasses genetics

D. Involve changes in the X-chromosome
E. Readily detected by karyotype
analysis
MCQ A.13.10 The Rare-Variant-Common
Disease Hypothesis suggests that:

A. Common psychiatric disorders areassociated with an accumulation ofrare mutations
B. Common psychiatric disorders are
due to the addition of multiple common risk alleles
C. It is rare for common diseases tohave a genetic etiology
D. Genes and environments are interacting through epigenetic mechanisms
E. Genome-wide association studies
are necessary to determine genetic
etiology

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IACAPAP Textbook of Child and Adolescent Mental HealthANSWERS

MCQ A.13.1

Answer: D

MCQ A.13.2

Answer: A

MCQ A.13.3

Answer: D

MCQ A.13.4

Answer: E

MCQ A.13.5

Answer: B

MCQ A.13.6

Answer: D

MCQ A.13.7

Answer: E

MCQ A.13.8

Answer: C

MCQ A.13.9

Answer: B

MCQ A.13.10 Answer: A
MCQ A.13.11 Answer: D
MCQ A.13.12 Answer: D

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