PERSPECTIVESOPINION

Integrating ethics and science in theInternational HapMap Project
The International HapMap Consortium*
Genomics resources that use samples fromidentified populations raise scientific, socialand ethical issues that are, in many ways,
inextricably linked. Scientific decisions about
which populations to sample to produce the
HapMap, an international genetic variation
resource, have raised questions about therelationships between the social identities
used to recruit participants and the biologicalfindings of studies that will use the HapMap.
The sometimes problematic implications of
those complex relationships have led toquestions about how to conduct genetic
variation research that uses identified
populations in an ethical way, including how
to involve members of a population in
evaluating the risks and benefits posed foreveryone who shares that identity. The ways
in which these issues are linked is increasingly
drawing the scientific and ethical spheres ofgenomics research closer together.

resource to facilitate future studies that relate
human genetic variation to health and disease.
The Project raises many ethical issues because
it will allow researchers to compare patterns ofvariation among both individuals and populations. Throughout the Project, ethicists andsocial scientists have worked collaboratively
with geneticists to address these issues (members of the International HapMap Consortium
are listed in BOX 1).
This article provides an overview of the
ethical, social and cultural issues raised by theInternational HapMap Project and describes
how the Project is addressing them. The specific processes that were used to engage communities or consult with the public in thelocalities where people were approached to
donate blood samples, as well as the principal
findings that emerged from those processes,
will be described in separate publications.
Scientific rationale

For many biomedical research projects, coordinating the work on the study design and theassociated ethical issues presents serious challenges. Frequently, ethical concerns are identified and addressed only after the researchgoals have been stated and the study has
been designed. Alternatively, in large projects, a separate team of ethics advisers mightwork solely on that aspect of the study.
Here, we describe how in a multi-centre,
multi-nation collaborative project — theInternational HapMap Project — ethical considerations were identified and addressed fromits inception1. The HapMap Project is a majorinternational research effort to construct a

NATURE REVIEWS | GENETICS

Any two humans are approximately 99.9%
identical in their DNA sequences2, but the
0.1% by which they vary contributes todifferences in their risk of getting certain
diseases and their responses to drugs, infectious agents, toxins and other environmental
factors3. Finding the genetic variants that
influence disease risk and drug response isnecessary to understand how genetic and environmental factors interact to influence health.
Although the road from scientific discovery to
improved health outcomes can be long, understanding these factors should eventually lead tobetter methods of prevention, diagnosis andtreatment.

The scientific design of the International
HapMap Project has been described elsewhere1 (see online links box for information
about the project). The Project’s rationale isbased on the finding that many sets of adjacent SNPs have been passed down throughthe generations largely intact, resulting instrong associations among SNP alleles (variants) in chromosomal regions4. A set of associated SNP alleles in a chromosomal region is
known as a haplotype. Most regions have only
a few common haplotypes, which account formost of the genetic variation in these regions.
So, much of the information about patternsof variation in a region can be obtained bylooking at just a few ‘tag’ SNPs in that region
instead of all of them5–7.
The HapMap will describe the common
patterns of human genetic variation by identifying the chromosomal regions with sets ofstrongly associated SNPs (the haplotypes) andthe SNPs that identify (tag) them. Researchers
will use the tag SNPs from the HapMap tocompare a group of people with a disease (forexample, diabetes) with a group of people
without it. In most regions, both groups will
have similar haplotype frequencies. However,regions with alleles that affect the disease will
have a higher frequency of haplotypes associated with the disease in the affected group. As
a result, researchers will be able to scan theentire genome by genotyping only approximately 500,000 tag SNPs, and not all 10 million common SNPs. Similarly, researchers
will be able to examine regions of interest thatare identified from other studies by looking at
only a fraction of the SNPs in those regions.
The HapMap will therefore greatly reduce thecost of whole-genome scans for ASSOCIATIONSTUDIES and will facilitate more targeted association, candidate-gene, FAMILY-LINKAGE and8
ADMIXTURE-MAPPING STUDIES .
Project history and organization

Public discussion of a human haplotype
map began in 2001 at a meeting attended bygenetics and genomics researchers, experts
in the ethical, legal and social implications

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Box 1 | The International HapMap Consortium
The International HapMap Consortium is a partnership of scientists andfunding agencies from Canada, China, Japan, Nigeria, the United Kingdom
and the United States to develop a public resource that will help
researchers find genes that are associated with human health and disease.
The following authors are members of this group (institutions andauthors are listed alphabetically (except for chairs/co-chairs, who are listed
first); author affiliations are detailed in the online supplementary
information S1 (box)):Ferretti, Martin Leboeuf, Michael S. Phillips and Andrei Verner |University of California at San Francisco and Washington University:
Pui-Yan Kwok, Shenghui Duan, Denise L. Lind, Raymond D. Miller, John
P. Rice, Nancy L. Saccone, Patricia Taillon-Miller and Ming Xiao |University of Tokyo and RIKEN: Yusuke Nakamura, Akihiro Sekine,
Koki Sorimachi, Toshihiro Tanaka, Yoichi Tanaka, Tatsuhiko Tsunoda
and Eiji Yoshino | Wellcome Trust Sanger Institute: David R. Bentley,
Panos Deloukas and Don Powell

Ethical, Legal, and Social Issues Group

Analysis groups

Vanderbilt University: Ellen Wright Clayton (co-chair) | University ofMontréal: Bartha M. Knoppers (co-chair) | Chinese Academy of Social
Sciences: Renzong Qiu | Genetic Interest Group: Alastair Kent | Howard
University: Georgia M. Dunston | Kyoto University: Kazuto Kato |Nagasaki University: Norio Niikawa | University of Oklahoma: Morris
W. Foster | University of Ibadan: Isaac F. Adewole | Wellcome Trust:
Jessica Watkin

Broad Institute: David Altshuler, Mark J. Daly and Stephen F. Schaffner |Cold Spring Harbor Laboratory: Lincoln D. Stein, Fiona Cunningham,
Ardavan Kanani and Gudmundur A. Thorisson | Johns Hopkins
University School of Medicine: Aravinda Chakravarti, Peter E. Chen,David J. Cutler, Carl S. Kashuk and Shin Lin | University of Oxford: Peter
Donnelly, Jonathan Marchini, Gilean A. T. McVean and Simon R. Myers |University of Oxford/Wellcome Trust Centre for Human Genetics: Lon
R. Cardon, Gonçalo R. Abecasis, Andrew Morris and Bruce S. Weir | US
National Institutes of Health: James C. Mullikin, Stephen T. Sherry andMichael Feolo

Community Engagement/Public Consultation and Sample
Collection Groups
Beijing Normal University and Beijing Genomics Institute: Houcan
Zhang and Changqing Zeng | Health Sciences University of Hokkaido,
Shinshu University and Eubios Ethics Institute: Ichiro Matsuda,
Yoshimitsu Fukushima, Darryl R. Macer and Eiko Suda | Howard
University and University of Ibadan: Charles N. Rotimi, Clement A.
Adebamowo, Toyin Aniagwu, Patricia A. Marshall, Olayemi Matthew,
Chibuzor Nkwodimmah and Charmaine D. M. Royal | University of
Utah: Mark F. Leppert and Missy Dixon

Populations and Ethical, Legal, and Social Issues Initial
Planning GroupDavid L. Valle (chair), Ellen Wright Clayton (co-chair), Lynn B. Jorde (cochair), John W. Belmont, Aravinda Chakravarti, Mildred K. Cho, Troy
Duster, Morris W. Foster, Marla Jasperse, Bartha M. Knoppers, Pui-Yan
Kwok, Julio Licinio, Jeffrey C. Long, Patricia A. Marshall, Pilar N. Ossorio,
Vivian Ota Wang, Charles N. Rotimi, Charmaine D. M. Royal, Patricia
Spallone and Sharon F. Terry

Genotyping centres
Baylor College of Medicine and ParAllele BioScience: Richard A. Gibbs,
John W. Belmont, Paul Hardenbol, Thomas D. Willis and Fuli Yu | Broad
Institute: David Altshuler and Stacey B. Gabriel | Chinese HapMap
Consortium: Huanming Yang, Lan-Yang Ch’ang, Wei Huang, Bin Liu, Yan
Shen, Paul Kwong-Hang Tam, Lap-Chee Tsui, Mary Miu Yee Waye, Jeffrey
Tze-Fei Wong, Changqing Zeng and Qingrun Zhang | Illumina: Mark S.
Chee, Luana M. Galver, Semyon Kruglyak, Sarah S. Murray and Arnold R.
Oliphant | McGill University and Génome Québec Innovation Centre:
Alexandre Montpetit, Thomas J. Hudson, Fanny Chagnon, Vincent(ELSI) of genetics and genomics research,
consumers, community members and funding agency representatives (see online links
box for 2001 HapMap agenda and participants). Although most participants agreed
that haplotype mapping would help speed
up the discovery of genes that affect at least
some diseases, others expressed concerns
about the ethical and social implications ofsuch an initiative.
A recommendation was made to proceed
but with a commitment to integrate ethical,
social and cultural considerations into allphases of the Project. To this end, two initial

4 6 8 | JUNE 2004 | VOLUME 5

SNP discovery
Baylor College of Medicine: Richard A. Gibbs, John W. Belmont, Erica
Sodergren and George M. Weinstock | Broad Institute: Bruce W. Birren |Washington University: Richard K. Wilson and Lucinda L. Fulton |Wellcome Trust Sanger Institute: Jane Rogers

Scientific management
Chinese Academy of Sciences: Hua Han | Chinese Ministry of Scienceand Technology: Hongguang Wang | Genome Canada: Martin Godbout
and John C. Wallenburg | Génome Québec: Paul L’Archevêque and Guy
Bellemare | Japanese Ministry of Education, Culture, Sports, Science andTechnology: Kazuo Todani, Takashi Fujita and Satoshi Tanaka | The SNP
Consortium: Arthur L. Holden and Eric H. Lai | US National Institutesof Health: Francis S. Collins, Jean E. McEwen, Vivian Ota Wang, Lisa D.
Brooks, Mark S. Guyer, Elke Jordan, Jane L. Peterson, Jack Spiegel,
Lawrence M. Sung and Lynn F. Zacharia | Wellcome Trust: Karen
Kennedy, Michael G. Dunn, Richard Seabrook, Mark Shillito, Barbara
Skene and John G. Stewart

Methods Initial Planning Group
Eric S. Lander (chair), Eric H. Lai (co-chair), Deborah A. Nickerson (cochair), Gonçalo R. Abecasis, David Altshuler, David R. Bentley, Michael
Boehnke, Lon R. Cardon, Mark J. Daly, Panos Deloukas, Julie A.
Douglas, Stacey B. Gabriel, Richard R. Hudson, Thomas J. Hudson,
Leonid Kruglyak, Pui-Yan Kwok, Yusuke Nakamura, Robert L.
Nussbaum, Charmaine D. M. Royal, Stephen F. Schaffner, Stephen T.
Sherry, Lincoln D. Stein and Toshihiro Tanaka

planning groups were established: a Methods
Group to consider the technical requirements
and a Populations/ELSI Group to consider
ethical and sampling issues (see online links
box for 2001 HapMap working groups roster). The latter group included genomics andpopulation genetics researchers and ELSI
experts. The inclusion of ethicists in the initial meeting and the immediate formation of
the combined working groups to decide fundamental questions of study design are
examples of the deliberate integration of scientific and ethical considerations from the
beginning of the Project.

The Populations/ELSI Group was given
responsibility for two interrelated scientificand ethical questions: how to sample human
genetic variation to identify common haplotypes, and whether to name the populations
from which the donors came. Initially, Group
members were from the United Kingdom,
Canada and the United States — the initialcountries that gave financial support to theProject. After Japan and China had secured
financial support, both the Methods Groupand the Populations/ELSI Group were succeeded by new groups with members fromeach participating country.

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PERSPECTIVES
The current ethics group, the International
HapMap ELSI Group, makes recommendations to the Project’s Steering Committee(which includes some members of the ELSIGroup). Some ELSI Group members also
serve on the Project’s Communications Groupto ensure that attention is paid to ethical issues
in Project publications and that the descriptions of the scientific design and findings
reflect sensitivity to social and cultural issues.
In some of the countries that are involved,
committees that make recommendations to
the funding agencies also oversee the project.
Local ethics committees had final authority
over the way the samples were collected.
Sampling strategy

Most evidence indicates that modern humans
appeared in Africa more than 150,000 years
ago9. Some of the descendents of this groupremained in Africa, whereas others migrated,
eventually reaching all parts of the world.
Much of the genetic variation that is present
in the original ancestral population in Africa
was therefore carried into the descendant
populations and is now in all world populations10. Any one population includes approximately 90% of the genetic variation that ispresent throughout the world11,12.
Population expansions, BOTTLENECKS, FOUNDER
EFFECTS and natural selection have influenced
the frequency of variants and haplotypes in
populations in different parts of the world12,13.
So, most common haplotypes are expected to
be found in all human populations, but thefrequencies of particular haplotypes will vary
among populations4. Mutation and recombination have created new haplotypes since themigration out of Africa and, therefore, somevariants and haplotypes are found only inindividuals with ancestry from particulargeographical regions.
Population differences in haplotype frequencies are important for discovering genesthat are related to health and disease. For
example, an association study can have falsepositive results if haplotypes in chromosomal
regions other than those with the causal alleles
differ in frequency between individuals withthe disease and healthy controls14; this problem
often occurs when different proportions ofcases and controls have been recruited fromdifferent populations. In addition, populations
that have experienced recent bottlenecks might
have longer haplotype lengths, potentiallymaking initial identification of associatedchromosomal regions more efficient15. On theother hand, shorter haplotypes (as is often seen
in African populations, reflecting their longer
history) might allow finer identification of thecausative regions.

NATURE REVIEWS | GENETICSBox 2 | Individual inclusion criteria
Sample donors had to be adults (as legally defined in each country) and competent to provide
informed consent. The Yoruba participants were required to have four Yoruba grandparents (asidentified by the donor). The Han Chinese participants were required to have at least three Han
grandparents. In Japan, where it is considered culturally insensitive to ask donors specifically
about the origins of their grandparents, individuals wishing to donate were simply told that theaim was to collect samples from people whose grandparents were from Japan.
Asking individuals to identify themselves, or their grandparents, as having a particular ancestry
will inevitably result in some imprecise or inaccurate assignments. In fact, as in many population
genetics studies, the ways in which the populations themselves were defined for the Project were
inexact. For example, the Centre d’Etude du Polymorphisme Humain (CEPH) samples werecollected in 1980, when most researchers did not consider it necessary to ask potential donors
how they self-identified or where their ancestors originated; it was merely generally known thatmost individuals in that community were of primarily northern and western European descent.
The lack of precise population definitions and ancestral geographical self-assignments is notproblematic for developing the HapMap because exact demarcations are not necessary for theway that the HapMap will be used, and the Project does not aim to define populations. No claims
are made about the genetic ‘purity’ of the sample sets or the populations of which donors are
members; such claims would be scientifically spurious, as human populations are the products ofcountless social, historical and demographic processes, and therefore can never be sharply defined.

Because the goal of the HapMap Project isto develop a tool that will help researchers to
discover the genetic contributors to healthand disease, a population-sampling strategy
was chosen to maximize the downstream
benefits of the Project for all populations —both sampled and un-sampled populations.
For the purposes of the Project, a ‘population’ is defined as a group of people with ashared ancestry and therefore a shared history and pattern of geographical migration.
(It is important to note, however, that on
the basis of this definition, many individuals
can claim membership of more than one
population, while some of those who claim
a particular population identity do not sharethe same biological ancestry; this situation
makes doing genetic variation research withidentified populations both scientifically andethically complex.) Although the globallycommon haplotypes could have been identified with samples from any one population,
studying samples from several populations
with different ancestral geographies, reflecting
different population histories, should makethe HapMap most useful for studies in many
populations.
For both scientific and ethical reasons,Project planners recommended choosing one
or more populations with ancestry fromAfrica, Asia and Europe, and at the same time
keeping open the possibility of adding populations with ancestry from other parts of theworld at a later date. The results of an initialstudy of samples that had already been collected from the Yoruba people (from Nigeria),
Japanese and Chinese individuals, and residents of the United States (Utah residents withancestry from northern and western Europe,collected in 1980 by the Centre d’Etude duPolymorphisme Humain, and known as the
CEPH samples) showed substantial similarities in the haplotype patterns of these populations, but differences in the frequencies andlengths of many haplotypes4. This indicatedthat a HapMap developed with samples fromthese populations or from others with similar
geographical ancestry would probably include
much of the common genetic variation that ispresent in the world, along with some moreregionally specific variation.
As part of a separate project, the US National Institutes of Health (NIH) are currently
arranging sample collection from several
other populations, including two in Africa,
one in Europe and several in the United Statesthat have complex histories of admixture.
These samples will be genotyped across a
few genomic regions to see how useful the
HapMap will be for a wider range of populations. If any of these other populations have
haplotype patterns that are substantially different from those in the populations initiallystudied to develop the HapMap, the samples
from those populations could be analysed
across the genome, which will become feasible
as genotyping costs continue to decline. Overtime, the HapMap might also be augmented
with data from other investigators.
Choosing the communities

On the basis of the recommendation of theworking groups that the HapMap be developed, at least initially, with samples from populations with African, Asian and European
ancestry, the Project is studying 270 DNA samples from 4 populations: 30 trios (two parents
and an adult child) from the Yoruba people of

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Ibadan, Nigeria; 45 unrelated Japanese in theTokyo area; 45 unrelated Han Chinese in
Beijing; and 30 trios from the Utah population
represented by the CEPH samples (BOX 2).
(Although Japanese and Chinese samples in
the pilot study had similar haplotype frequencies, Japanese and Han Chinese samples areboth being included because of the interest offunding agencies in Japan and China to use
samples from their own majority populations.) Although the samples come from large
populations with imprecise boundaries, they
are appropriate for the Project because thepurpose is to create a resource that can be usedin populations throughout the world, and not
to ‘define’ particular populations or to study
population relatedness.
The HapMap could have been developedwith some of the same sets of stored samples
that were analysed in the already-mentioned
preliminary study by Gabriel et al.4, or withstored samples that had already been collected from other populations; however, theconsent processes that were used for mostpreviously collected samples (except for the
CEPH samples) were judged to be inadequate for the HapMap Project because they
had not included discussions about sharing
samples with other investigators, about samples being used for genetic variation researchthat was not disease-specific or about the possibility that such research might raise groupbased concerns. So, new samples from Nigeria,
Japan and China were collected specifically for
the Project, with community-consultation andconsent processes that addressed those issues.
For the CEPH, all living donors of the previously collected samples were contacted toobtain consent to have their samples included in the Project, and the local Institutional Review Board (IRB) gave permission to
include samples from deceased CEPH donors.
Including the CEPH samples reflected
researchers’ desire to build on the foundationof many earlier studies that used those samples, including the human genetic linkage
map16. In addition, the Utah researchers whocollected the CEPH samples had maintained
long-term trust relationships with mostdonors, making it feasible to contact them
about the Project.
Because the HapMap could be developedscientifically with samples from any populations in Africa and Asia, the decisions about
which specific communities to approachfor the new samples that were required by
the Project were based on ethical and practical considerations. Researchers at Howard
University in Washington DC and at the University of Ibadan in Nigeria had already established research collaborations and had built a

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relationship of trust with the Yoruba people
from the Aba Alamu community in Ibadan.
Chinese investigators collected samples in the
Beijing Normal University residential community because it represents a diverse, yetsocially cohesive, population that is composedof mostly Han people from nearly every
province in China who have a range of educational, occupational and socioeconomic backgrounds. In addition, many members of that
academic community were familiar withresearch and research ethics that formed thefoundation for discussions about the HapMap
Project. Japanese researchers collected samples
from five different communities in Tokyo(drawing people from many parts of Japan)
in which participants were accustomed tobeing recruited for biomedical studies.

“Although there aredifferences among
populations … it isimportant that the findingsof the HapMap Project
not be over-simplified toperpetuate social andhistorical stereotypes.”

Identifying the populations

Although the HapMap will include no personal identifiers or medical information
about sample donors, each sample will beidentified by the population from which itcame. The scientific rationale for identifying
the populations is that differences in haplotype frequencies and lengths among populations will be important for how data from theProject are used. In chromosomal regions inwhich the populations have similar haplotype
frequencies, the HapMap and tag SNPs will be
the same for all the populations; in regions inwhich the populations differ in haplotype frequencies, the HapMap and tag SNPs might
differ among the populations. Having the
population information will make it possible
to choose the most efficient sets of tag SNPs to
use in future association studies in particular
populations. For example, knowing that one
particular set of HapMap samples came fromthe Japanese would inform which tag SNPs
might be most useful in a drug-response study
in people of Japanese descent or in people
from other populations found to have similar
haplotype frequencies.

From an ethical point of view, removing
population identifiers could create a false
sense of protection from collective risks. As theresearchers and institutions involved in the
HapMap Project are named in grants and publications, it would be easy to guess the populations from which donors were recruited. It
would also not be difficult to discern from previously collected data sets the identity of these
populations. Rather than allow donors toassume that their population identities were
protected or allow other researchers to infer
those identities (and construct their own,
perhaps inaccurate, interpretations of how
those identities relate to genetic variation),
naming the populations was thought to be
more ethically appropriate. This approachgave donors the ability to evaluate the implications of inclusion and to have some input
into how they wanted their population
named. Naming the populations will also
allow HapMap researchers and ethicists toprovide better context for others for interpreting the biological significance of genetic
findings that are associated with particular
population identities.
Naming the populations does, however,
have important ethical and social ramifications. For example, the HapMap will makeit more efficient to study population history
and make inferences about population relatedness. It would be impractical, and evenundesirable, to limit the type of research thatcan be done with the HapMap to ‘purely’
biomedical studies, because populationhistory research can be useful biomedicallyand because the line between biomedical andpopulation-history research is often imprecise. For the particular populations that areincluded in the HapMap, as for most large,
loosely defined populations, the fact thatthe HapMap will facilitate population-history studies raises few concerns. For others,
however, such as many American–Indian
tribes and small isolated indigenous groups,
population-history findings from genetic
studies of members’ samples could conflictwith religious or cultural understandings
about their origins, or legal or political claims
that relate to land or items of cultural patrimony17. For these groups, the decision to
construct the HapMap with samples fromnamed populations could signal renewedemphasis on a disfavoured aspect of genetic
variation research.
Indeed, it is mainly for these reasons that no
samples from members of American–Indian
tribes are included among those being initiallyanalysed for the Project. In 2003, the National
Human Genome Research Institute (NHGRI)
convened a meeting with several leaders in the

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PERSPECTIVES
American–Indian health-research community to explore the extent of interest among
American–Indians in participating in this typeof research. Most of the attendees were notinterested in tribal participation in such a study
at this time, citing concerns that the HapMap
will facilitate population-history studies andcomparisons among populations. They did,
however, suggest that it might be appropriate
to reconsider participation later, on the basisof what is learned from studies of haplotype
patterns in other populations and the likelihood that discoveries of genes associated withdiseases and drug responses in those populations would or would not benefit people ofAmerican–Indian ancestry.
Despite the many non-biological factorsthat contribute to population identities,
the way that a population is labelled in the
HapMap and described in publications will
have implications for all members of the population, as all of them (and all members ofclosely related populations) might be affectedby the interpretation and use of findings offuture studies that use the HapMap18. If, forexample, future studies lead to the discovery
of genetic variants associated with obesity, thefrequencies of those variants could be determined for each population in the HapMap
sample sets. If a higher frequency of obesityassociated variants were found in the samples
from one population and this information
was then erroneously applied to all or most ofits members and to members of closely related
populations, entire populations could be stigmatized or suffer discrimination19, especiallyin places where individuals with ancestry fromthose populations are a minority.
This risk of group stigmatization is inherent in any study of samples from identified
populations. Nevertheless, the limitations andambiguities of population identifiers must
continually be emphasized. For example, theindividuals sampled from the residential
community at Beijing Normal University do
not represent all people in China, where there
are 56 officially recognized ethnicities. Nor do
the people sampled in Ibadan, Nigeria, represent all Africans or even all Yoruba people.
Such limitations will be noted explicitly in
Project publications that report the study’s
findings, and researchers who do futurestudies with these samples or with Project
data will also need to be aware of thesecomplexities when designing and reporting
their studies. Although there are differencesamong populations in the frequencies ofsome genetic variants, it is important thatthe findings of the HapMap Project not be
over-simplified to perpetuate social andhistorical stereotypes.

NATURE REVIEWS | GENETICS

Informed consent and privacy

ELSI experts and geneticists developed ageneral template for documents to obtain
informed consent from the donors of the
new samples and for re-consent from the living donors of the CEPH samples. The consent
forms were then modified by the researchers
who interacted with the communities to makethem culturally appropriate before being submitted for approval by local ethics committees. The new samples were collected withpopulation and sex identifiers, but without
links to individual donors. Although the collectors of the CEPH samples do retain links
to individuals, which made it possible to seek
the re-consent to have the samples used for the
HapMap, these links are held in strict confidence and will not be shared with HapMap
Project researchers or users, or with the repository where the samples are stored.

“Community consultation
for the HapMap was done
under the auspices of local
governments and ethics
committees, taking into
account international andlocal ethical guidelines.”
The HapMap will include no medical orother phenotypic information about the sample donors. Such information is unnecessary
because the HapMap will simply be a description of patterns of genetic variation; it cannot
be used by itself to find disease-associatedgenes. To further diminish individual privacy
risks, more samples were collected frommembers of each population than were madeinto cell lines or used so that no one — noteven the sample donors — can know whether
any particular person’s sample was actuallyused to develop the HapMap.
Nonetheless, extensive genomic information about each individual donor will eventually be contained in the HapMap database,in the form of millions of SNP genotypes foreach person. Moreover, the data will beaccessible to anyone with an Internet connection through the HapMap web site (seeonline links box) and through the National
Center for Biotechnology Information public database, dbSNP (see online links box).
However, it will be extremely difficult foranyone to link any genomic data in the

HapMap database to a specific person. This
could happen in only two ways. One is if
someone thought a certain person’s data
were included in the HapMap database, andif they obtained blood or another tissue
sample from that person, genotyped it andcompared the information with the data in
the HapMap database. Alternatively, a match
could be discovered if somebody compared
the information in the HapMap databasewith genetic information known to be froma donor whose data were already in anotherdatabase.
The risk that individual sample donors will
suffer a breach of privacy or discrimination on
the basis of their genetic information, although
not absent, is very small. As genotyping costs
decline and individuals are more commonly
genotyped for clinical purposes, it might one
day become more feasible to identify individual donors whose genotypes are part of public
databases such as the HapMap. It is, however,unlikely to be worth the cost and effort to try toobtain personal information in this way.
Community engagement

Because the HapMap will allow comparisonsof patterns of genetic variation among populations, the initial Populations/ELSI Group
recognized that some meaningful process ofcommunity engagement, or public consultation (the term preferred in Japan), would benecessary before individual informed consent could be obtained, and that this process
should continue after the samples were collected. Whereas a ‘population’ refers to a groupof individuals who have a common geographical ancestry, a ‘community’ is a group with amultitude of local units of social organization
within a population. Importantly, individuals
might consider themselves to belong to many
communities (both the collective of individuals at Beijing Normal University and the residents of the area where samples were collected
in Japan include people from many places ineach country) or to share a broader identitythat subsumes many communities (such as the‘Han Chinese’, ‘Yoruba’ or ‘Japanese’ identities).
The need for meaningful community
involvement in any type of biomedical researchwith named populations has become increasingly recognized20–26. Acknowledgement of
this need grew noticeably following discussionof the proposed Human Genome Diversity
Project, an effort intended to sample human
genetic variation globally for various scientificpurposes — primarily anthropological — thatgenerated considerable controversy27,28. Muchof the controversy arose as a result of misunderstandings brought about by insufficient
community involvement29.

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PERSPECTIVESExtensive discussions have taken place in
the international bioethics community about
the need for community involvement in biomedical research with named populations.
The need for community engagement is especially strong for genetic variation researchsuch as the HapMap, which is not focused on
any particular disease30,31; for this reason, it
was made a central part of the Consortium
plan for the HapMap project1. International
ethical guidelines now support the active
involvement of communities in such studies32–36. The Human Genetic Cell Repositoryof the NIH National Institute of General
Medical Sciences, at the non-profit Coriell
Institute for Medical Research, where the
HapMap samples are stored, strongly recommends (and requires for US populations)some form of community consultation before
it will accept samples from identified populations for its genetic variation panels (seeonline links box for Human Genetic Cell
Repository submission information).
Although the opinions of an entire population cannot be generalized from the views
expressed by a small set of individuals in one
specific locality22, the goal of community
engagement or public consultation for the
HapMap Project was more circumscribed:
that was, to give people in the communities
that were being approached for participation
an opportunity to share with investigators
their views on the ethical, social and culturalissues that the Project raises for them andtheir communities, and to provide some
input into the way their samples would becollected and described.

Community engagement is distinct from
community consent, in which community
leaders, or even an entire community, can vetoa research project37. For example, American–
Indian tribes, as sovereign nations, require
formal tribal approval (a form of community consent) before investigators can recruit
research participants within tribal jurisdictions or specifically because they are tribal
members38. Although this requirement is
not present for any communities that wereapproached for the HapMap, had significant
opposition in a particular community beenencountered, no samples would have beencollected there. In Ibadan, Nigeria, where
there are organized community structures,and community leaders must be consulted
before research is done, those processes wererecognized and followed.
Community consultation for the HapMap
was done under the auspices of local governments and ethics committees, taking into
account international and local ethical guidelines32,33,35,36,39–43. Separate articles will describein greater detail the community-consultation
processes in each of the localities and what waslearned from them. Community engagement
and sample collection in Nigeria were supported by the NHGRI and carried out by USinvestigators with collaborators in Nigeria. In
China and Japan, although the funding agencies had not initially budgeted for community-consultation activities, flexibility was
found to allocate funds for this purpose. All of
the community-engagement or public-consultation teams included individuals with expertise in genetics, bioethics and social science.

Box 3 | Sample storage
Cell lines were made from the blood samples and will be maintained at the National Institute ofGeneral Medical Sciences Human Genetic Cell Repository at the non-profit Coriell Institute(see online links box), which currently houses the world’s largest collection of human cell lines
available for general research. The cell lines and DNA from the samples will be made available toacademic, government and commercial researchers around the world who have protocols that areapproved by relevant ethics committees and that are determined by the Coriell Institute’s
Institutional Review Board to be consistent with the terms of the informed consent documents. A
duplicate set of the Han Chinese samples will be retained in China, as required by Chinese law.
The samples stored at the Coriell Institute will be of enormous interest to researchers for many
years in many types of study. The consent forms authorize a range of such studies, including
population-history and cell line gene-expression research. Some such studies might raise risks
that cannot be foreseen — a point made in the consent documents and discussed with donors. In
general, however, the risks associated with such future research are unlikely to be different inkind from those raised by the HapMap itself. For example, as the samples are not associated withany medical information, they cannot be used by themselves to find genes related to potentiallystigmatizing diseases or traits.
As no personal identifiers are included with any of the new samples (and the links to the Centred’Etude du Polymorphisme Humain donors’ identities are not available to the repository), it willbe essentially impossible to contact donors to seek their re-consent for future studies. The
absence of personal identifiers will also make it, in effect, impossible for individual donors towithdraw their samples.

4 7 2 | JUNE 2004 | VOLUME 5

The principal investigators for each community-consultation team are members of the
Project’s Steering Committee so that information flows between the researchers and theparticipating localities.
Limitations and problems

Community consultation has many limitations44. The form and outcome of community
consultation for the HapMap Project varied
by location, and practical problems arose that
required flexibility. In Nigeria, it took morethan six months to obtain the necessary ethics
committee approvals from each collaborating
institution, which reduced the time available for pre-sample-collection communityengagement activities; follow-up activities,
including interviews, focus groups, town
meetings and a community survey, continued
after the samples were collected. In China, theoccurrence of the SARS epidemic in the middle of the process similarly required compressing many of the community-engagement
activities into a shorter time frame, although
investigators still completed all of the planned
activities, including numerous interviews andfocus groups, and received input from a
range of people from many sectors of society.
In Japan, a funding agency’s concerns thatthe study would proceed for more than a year
without any Japanese samples being studied(genotyping had begun on the previously
collected CEPH samples while community
engagement and sample collection proceededat the three other sites) led to some streamlining of the process during the pre-sample
collection phase. On the other hand, someconcerns were expressed in Japan that theneed to obtain the samples on the same
timetable as the Yoruba and Han Chinese
samples did not allow optimal time to engage
the public fully45. In fact, at all the sites where
new samples were collected, tension occurred
between the need for adequate time to engage
communities and the need to obtain samples
on the timetable driven by scientific andfunding practicalities.
Nevertheless, the genotyping centres andfunding agencies made considerable compromises to accommodate the needs of thecommunity-consultation processes. The community work increased the Project’s expense.
The genotyping centres had to wait more than
one and a half years after the Project’s official
launch to receive DNA from all the samples.
This delay required them to alter aspects of
their original scientific plan, it increased the
genotyping costs and created new and unexpected challenges. For example, the delay insample availability resulted in much genotyping being done on the CEPH samples (whichwww.nature.com/reviews/genetics

PERSPECTIVES

Box 4 | Sample collection among the Yoruba
It was important from a scientific point of view to include in the International HapMap Project atleast one population that had recent African ancestry, as these populations contain more genetic
variation than other world populations. It would have been much cheaper and easier for the
Project to have studied a set of African samples that had already been collected, to have sought
samples from one of the large US African immigrant communities or to have sought samples fromAfrican–Americans (who have haplotypes and haplotype frequencies similar to the Yoruba)4.
These approaches, however, would have raised ethical issues of their own. Collecting samples in
Nigeria was therefore not an instance of exploiting a vulnerable population to get samples thatwere too difficult to obtain elsewhere. The decision was also informed by international guidelinesthat specifically endorse the inclusion of developing countries in genetics research33,36,46.
Donors in Nigeria were each given an equivalent of ~US $8.00 and multivitamins worth~US $4.00 to compensate them for their time and travel — a standard amount for participationin research involving blood draws in that part of Africa. Prospective donors were not told thatthey would be compensated until after they had arrived to donate, to guard against the possibility
that they would be induced to participate by the prospect of material benefit. The Project also
provided some immediate benefits to the participating community. Staff on the local researchteam received training in research ethics issues, including procedures to strengthen community
processes for obtaining informed consent. Funds were provided for further primary andpreventive health-care services in the community, and more substantial support for local healthcare infrastructure and equipment to enhance local research capabilities is being negotiated with
the Community Advisory Group.
Consistent with international guidelines stating that any knowledge generated from researchthat is done in a resource-poor country should be made reasonably available for the benefit of its
people33, the HapMap Project data will be placed in the public domain and will be accessible toresearchers around the globe. These researchers will include, among others, investigators who
study genetic factors that influence individual risk for infectious diseases, such as malaria andtuberculosis, that remain high-priority health concerns in Nigeria and other resource-poor
countries. Although translating the understanding of these genetic factors into improved healthoutcomes is probably going to be a long, arduous process, the benefits would not be possible in
the absence of research.

did not have to be newly collected) before
genotyping on the other samples could begin.
This created the risk of misperception on thepart of the public that higher priority was
being given to the CEPH samples when thisdisparity reflected merely the ethical necessity
to take more time for community consultation where new samples were being collected.
The delay in the availability of the Yoruba
samples (which are expected to show shorterrange associations among SNPs and greater
haplotype diversity than those from the otherpopulations) also delayed the development of‘stopping rules’ for the Project, which specify
when adequate coverage for all the populations
will be achieved.
Whether the extra time, effort and expense
incurred from the engagement and consultation processes will be counterbalanced byincreased public trust remains to be seen. But
the experience so far indicates that asking
people respectfully about participating in
projects of this type, providing complete, balanced and accurate information, giving thema chance to express their views, and (where
possible), incorporating their input, need not
unduly impede research. Indeed, it can createa climate in which research proceeds in an
atmosphere of openness and trust26.

NATURE REVIEWS | GENETICS

Community advisory groups

Careful guidelines on sample storage andaccess were an integral part of the Project, as
they have important research and ethicalimplications (see BOX 3 for a summary).
In anticipation of the possibility that concerns might arise about future uses of thesamples despite detailed guidelines in the consent forms, a Community Advisory Group(CAG) was established in each community
where new samples were collected. Each CAG
will function as a liaison between the community from which the samples were collected and the Coriell Institute. The Coriell
Institute will not distribute samples to investigators if the proposed research is inconsistent
with the terms of the donors’ consent, andwill consult the CAGs if any proposed use of
the samples raises questions. The CAG ineach locality will hold periodic meetings. The
Coriell Institute will provide up to US $1,000
per year per site to defray expenses, and willproduce quarterly reports and an annual
newsletter describing how the HapMap andthe samples are being used.
With this structure in place, it seems
improbable that a community would seek
to withdraw its samples from the repository
except in extraordinary circumstances.

However, pursuant to a written policy of theCoriell Institute, if a CAG wishes to withdraw
its community’s samples, in response to theviews of a substantial portion of the community and after careful consideration, thatrequest will be honoured. The genotype data
already in the HapMap database, however,
could not be withdrawn (even if removed
from the Project web site or the public SNP
database, dbSNP), because they would alreadyhave been widely distributed.
The purpose of the CAGs is to ensure thatthe community-engagement or public-consultation processes continue after the samples arecollected. The effectiveness of the CAG mechanism, similar to the effectiveness of the community-engagement and public-consultation
processes, can only be assessed over time.
Profits, patents and data release

It is hoped that the HapMap Project will eventually benefit the health of all people. Most of
the benefits, however, will not be immediately
apparent, and some might take years to materialize. So, in the short term, the main beneficiaries will not be sample donors, their families ortheir communities, but researchers, who will
gain professional rewards and companies, thatwill be able to develop drugs, diagnostic tests orother commercial products from researchusing the HapMap. No commercial products
will be developed as part of the Project, however, as the HapMap is merely a resource thatcatalogues the common patterns of genetic
variation. So, although future studies that use
information from the HapMap might generate
profit, the HapMap Project itself will not do so.
In addition, the Coriell Institute does not allow
investigators to commercialize the samples.
Glossary
ADMIXTURE MAPPING STUDY

Mapping genes that affect a phenotype on the basis of thelinkage disequilibrium generated in a population that isformed by admixture between groups that differ in allele
frequencies and the frequency of the phenotype.
ASSOCIATION STUDY

A set of methods that are used to correlate
polymorphisms in genotype to polymorphisms inphenotype in populations.
BOTTLENECKS

A temporary reduction in population size that mightcause the loss of genetic variation.
FAMILY-LINKAGE STUDY

A study that examines DNA sequence variants in families
having multiple members with a disease, to map the
genomic location of genes that affect the disease.
FOUNDER EFFECTS

A relatively high frequency of an allele in a population
because it was founded by a small set of individuals who
had the allele at a higher frequency than in the parent
population.

VOLUME 5 | JUNE 2004 | 4 7 3

PERSPECTIVESThe Project has adopted an interim protective strategy to try to ensure that no restrictive patents are filed by researchers who use
HapMap Project data. The individual genotype and haplotype data are initially being
made available under a click-wrap licence thatstates that users will agree to not reduce others’ access to the data and to share the data
only with others who have made the same
agreement (see online links box for information on genotype access registration); when
the Project is over (estimated to be at the endof 2005), all of the genotype and haplotype
data will be publicly released. Other data,such as SNP allele and genotype frequencies,
will be publicly released soon after they are
obtained (at the Project website and the public database, dbSNP; see online links box).
Project researchers will not seek patents on
the data that they generate for which they
have not demonstrated a specific use (such as
relating a particular haplotype to a disease)
and will not use the Project data for otherprojects in their laboratories before the data
are released.
Benefits and reciprocity

Each genotyping centre has been assigned
particular chromosomal regions to genotype
in all four sets of samples. Researchers in threeof the countries where samples were collectedor where re-consent was obtained (that is,Japan, China and the United States) will benefit by participating in the genotyping. Also,
the sample collection that took place in eachcountry was supported by funding agencies
in that country, except for Nigeria, where thatwork was funded by the NHGRI; although
local investigators engaged the communityand collected the samples, no local investigators will be involved in the genotyping. See
BOX 4 for a discussion of why, given thesecircumstances, it was appropriate to collectsamples in Nigeria.
Another question is whether spending US$120 million to create the HapMap is ethicallyjustified when much of the world’s population
lacks access to basic health care. The hope, aswith other research investments, is that theexpenditure will eventually prove to have been
well justified in terms of its benefits to world
health. But understanding patterns of genetic
variation and finding health-related genetic
variants are merely initial steps; researchers
must still discover how genes work and interact
with environmental factors in the disease
process and then must find a way of translatingthat knowledge into better health outcomes. It
is essential that the HapMap and studies thatuse it are not ‘over-hyped’ or used to reinforce
mistaken ideas of genetic determinism.

4 7 4 | JUNE 2004 | VOLUME 5

Conclusions

As medical research scales up case–control
and population-based studies that aim to
identify genetic and environmental contributions to complex diseases, ethical questions
will grow in number and complexity. Thosequestions will involve privacy, consent andother issues of concern to individual participants, issues related to the populations towhich those individuals belong and evenpotential effects on non-participating populations. In some instances, addressing risks andbenefits to populations might be as important
as weighing these concerns for individuals.
Although the process we have describedhere represents what we believe to be a usefulstarting point for similar future studies, we recognize that it is only a small step towards doing
more culturally sensitive genetics research.
Those who follow no doubt will improve on
these procedures. Ethical standards for the protection of participants in research are continually evolving and require experiences such as
the one we have described to explain the philosophical and practical foundations on whichthose standards are based. Only in this way canbioethics proceed as both an empirical and aphilosophical undertaking.
*Members of the International HapMap
Consortium are listed in Box 1.
Correspondence to Morris W. Foster at the
University of Oklahoma, Department of
Anthropology, 455 W. Lindsey, Room 520,
Norman, Oklahoma 73019-0535, USA.
e-mail: fost1848@msmailhub.oulan.ou.edu
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Acknowledgements
Full details of acknowledgements are given in the online supplementary information S2 (box). We thank many people who contributed to addressing the ethical, social and cultural issues in thisproject: J. Greenberg, R. Anderson, J. Beck and the staff of theCoriell Institute, M. Inaba, H. Zhao, Y. Wang, W. Hu, H. Zhao, Y.
Gao, Q. Zhang, Y. Zheng, D. Guan, W. Jiang, J. Li, Z. Li, W. Luo,K. Shen, X. Zhou, Y. Li, X. Feng, J. Ren, M. Deschênes, B.
Godard, S. Adeniyi-Jones, D. Burgess, W. Burke, T. Citrin, D.
Cowhig, P. Epps, K. Hofman, A. Holt, E. Juengst, J. Levin, A.
Obuoforibo, F. Romero, C. Tamura, Y. Wang, S. Olson, A. Peck, J.
Witonsky, E. DeHaut-Combs, S. Saylor, M. Gray, the people ofTokyo, Japan, the Yoruba people of Ibadan, Nigeria and the community at Beijing Normal University who participated in public consultations and community engagements, and the people in thesecommunities who were generous in donating their blood samples.
This work was supported in part by Genome Canada, Génome

Québec, the Chinese Ministry of Science and Technology, theChinese Academy of Sciences, the Natural Science Foundation ofChina, the Hong Kong Innovation and Technology Commission,
the University Grants Committee of Hong Kong, the Japanese
Ministry of Education, Culture, Sports, Science and Technology,
the Wellcome Trust, the SNP Consortium, the US National
Institutes of Health (FIC, NCI, NCRR, NEI, NHGRI, NIA, NIAAA,
NIAID, NIAMS, NIBIB, NIDA, NIDCD, NIDCR, NIDDK, NIEHS,NIGMS, NIMH, NINDS, OD), the W. M. Keck Foundation and theDelores Dore Eccles Foundation.

Competing interests statement
The authors declare that they have no competing financial interests.

Online links
FURTHER INFORMATION
Coriell Cell Repositories:
http://arginine.umdnj.edu/ccr/ccrsumm.html
Coriell Cell Repositories NIGMS Human Genetic Cell
Repository submission information:
http://locus.umdnj.edu/nigms/comm/submit/collpolicy.html
dbSNP: http://www.ncbi.nlm.nih.gov/SNP
HapMap — about the project:
http://www.hapmap.org/abouthapmap.html
HapMap — genotype access registration:
http://www.hapmap.org/cgi-perl/registration
International HapMap Project: http://www.hapmap.org
National Human Genome Research Institute — past
events 2001 HapMap agenda and participants::
http://www.genome.gov/10001685
National Human Genome Research Institute — past
events 2001 HapMap working groups roster:
http://www.genome.gov/10001685
SUPPLEMENTARY INFORMATION
See online article: S1 (box) | S2 (box)
Access to this links box is available online.

during the experiment, which ended not long
before the Community itself was dissolvedin 1880. The Community’s business enterprises became a joint stock company, whichstill exists as Oneida Ltd, an important multinational manufacturer of cutlery and flatware7. Even today, some descendants of theCommunity members live around the site of
their original home, some continuing towork for the company.
The children of the breeding experiment— the stirpicults — were carefully followed
up and were deemed to be superior in intellect, educational and professional achievement and physique8. The experiment and its
outcome were presented by two Community
members at the Second International Congressof Eugenics in 1921 (REF. 9). This large international gathering represented a high watermark for eugenics movements. However,despite the report on the Oneida experimentat such an important conference, it had little
or no influence on subsequent eugenic policies and practices. I suggest that this was
because of the difficulties in generalizing fromthe special context in which the experiment
took place.
Oneida, a utopian community

TIMELINE

A nineteenth-century experimentin human selective breeding
Martin Richards
A human selective breeding programme
took place in a North American bible
communist community, Oneida, between
1869 and 1879. It was probably the firstsuch breeding experiment of the modern
era, and for this reason, we might expect it
to have been influential for the subsequent
eugenics movements. Although it attracted
much attention in its day, its longer-term
influence seems to have been surprisingly
slight, largely because its specific context
meant that it was not a model that provided
an acceptable way to reach eugenics goals.

Francis Galton, generally regarded as thefather of eugenics (literally meaning ‘wellborn’), coined the term in 1883 and defined it
as “the study of the agencies under social control that improve or impair the racial qualities
of future generations either physically or mentally” according to a later Eugenics Society
poster1–3. He contributed substantially to that

NATURE REVIEWS | GENETICS

study through his own research on the familiesof men who were outstanding in intellect andin public life, and argued that intellectual abilities were mainly a matter of inheritance4,5. But,
the idea that intellectual ability and other mental characteristics were inherited and that there
could be dangers of transmitting hereditary‘taints’ already concerned medical men andothers much earlier in the nineteenth century 6.
It is these beliefs and the example of the effectiveness of selective breeding in animals thatprovided the backdrop for the Oneida selective
breeding experiment.
Oneida, an upper New York State Christianutopian community, was founded in 1848. In
the early years, the Community grew largely
through recruitment, but once it was wellestablished and financially secure, the decision was taken to have more children and to
breed them scientifically in a ‘stirpiculture’
experiment, the Community’s term for selective breeding. Some 58 children were born

Since its first colonial days, the United States
has had many utopian communities — communities in which people came together tolive and work, cooperatively bound together
by shared beliefs and commitments10. The firstcommunities were religious and were founded by groups who set out to live their chosen life in freedom in the New World, fleeing
religious persecution in Europe (BOX 1).
In contrast to earlier communities, Oneida
was a home-grown religious group, themembers of which were mainly at least second-generation European–Americans. Its
inspiration was religious, but several of theideas for their social organization came fromsecular roots in other communities, especiallyfrom the phalanxes of Fourier (BOX 1).
The founder of Oneida, John Humphrey
Noyes (1811–1886), came from an educatedbackground in Vermont, USA. Initially destined for a career in law, he was converted
at a revival meeting and went to Yale Theological Seminary to train as a preacher. Having
left the seminary, he began to espouse theheretical doctrine of PERFECTIONISM, and his
licence to preach was revoked. Perfectionists believed that through striving and communion with Christ, a sinless perfection
was attainable in this life11. This allowed aheaven on Earth to be established, and John
Humphrey Noyes became the prophet of that
unfolding kingdom. As the Bible says, “MyVOLUME 5 | JUNE 2004 | 4 7 5