4 Race and Genetics

R.A. Kittles, PhD, andJ Benn- Torres, PhD

CONTENTSINTRODUCTIONHow IS GENETIC VARIATION STRUCTURED?MEASURE AND USE OF GENETIC ANCESTRY

FINDING DISEASE SUSCEPTIBILITYGENES IN ADMIXED POPULATIONS

HAS NATURAL SELECTION SHAPEDGENETIC VARIATION?

CONCLUSIONREFERENCES

AbstractRace is an enigma, exhibiting no clear biological definition yet strong cultural

and SOCial meanings, particularly in the United States. However, the advent ofmolecular technology led to a new realization that within-group differences far~xceeded between-group differences. Our knowledge of human genetic varia-on has grown enormously over the past few decades. Single-nucleotide poly-morphisms (SNPs) are the most common form of DNA variation in the humangenome. At present, there are more than IO million SNPs in the human genome.At most genetic loci, African populations harbor some relatively common alle-les rhat are absent in non-African populations; however, most of the alleles thattioi common in non-African populations are also common in African popula-. ns. Given the genetic data now available across diverse human populallons,It IS becoming increasingly clear that the frequency of most genetic markersdo not vary much arnonz the major continental populations. However, a num-ber of studies that examine genetic variation across the genome have found that

From C d ch . M' 'ties: ontemporary Cardiology: Cardiovascular Disease in Racial an {:.c mc man I

Edited by: K.C. Ferdinand and A. Armani. DOl 10.10071978-1-59745410-0-4© Humana Press, a part of Springer SCience+Business Media, LLC 2009

81

4 Race and Genetics

R.A. Kittles, PhD, andJ Benn- Torres, PhD

CONTENTSINTRODUCTIONHow IS GENETIC VARIATION STRUCTURED?MEASURE AND USE OF GENETIC ANCESTRY

FINDING DISEASE SUSCEPTIBILITYGENES IN ADMIXED POPULATIONS

HAS NATURAL SELECTION SHAPEDGENETIC VARIATION?

CONCLUSIONREFERENCES

AbstractRace is an enigma, exhibiting no clear biological definition yet strong cultural

and SOCial meanings, particularly in the United States. However, the advent ofmolecular technology led to a new realization that within-group differences far~xceeded between-group differences. Our knowledge of human genetic varia-non has grown enormously over the past few decades. Single-nucleotide poly-morphisms (SNPs) are the most common form of DNA variation in the humangenome. At present, there are more than IO million SNPs in the human genome.At most genetic loci, African populations harbor some relatively common alle-les rhat are absent in non-African populations; however, most of the alleles thatare common in non-African populations are also common in African popula-lions. Given the genetic data now available across diverse human populations,It IS becoming increasingly clear that the frequency of most genetic markersdo not vary much arnonz the major continental populations. However, a num-ber of studies that examine genetic variation across the genome have found that

From: C?ntemporary Cardiology: Cardiovascular Disease in Racial and Ethnic MinoritiesEdited by: K.C. Ferdinand and A. Armani. DOl 10.10071978-1-59745410-0-4© Humana Press, a part of Springer SCience+Business Media, LtC 2009

81

821. Introduction

individuals with similar ancestral continental origins tend to cluster together,and in general, these clusters correspond to four continental groups: Sub-Saharan Africa, EuropelWestem Asia, Asia, and the Americas.Not withstanding the large amount of genetic variation shared across human

groups there is a small but significant fraction of polymorphisms that are quiteinformative for estimating biogeographic ancestry. Interestingly, individualsself-report as African-American due to skin color and the historical classifica-tion schema referred to as the "one-drop" rule which denotes an individual withan African ancestor as Black. The first striking feature observed is that 98%of the European Americans had over 90% European ancestry, while only 34%of the African-Americans possessed over 90% West African ancestry. Variancein genetic backgroundof study subjects is becoming more of an issue with theincreasing number of genetic association studies on complex disease. Differ-ences in genetic background among study individuals may impact the powerand reliability of genetic association studies. We suggest that ancestry be usedinstead of race. Genetic ancestry has several salient features which are usefulfor biomedical studies.

Key Words: Race; Genetics; AIMs; Population structure; Genetic ancestry;Genetic variation; Admixture.

1. INTRODUCTION

Knowledge from human genetic research continuously challenges thenotion that race and geneties are inextricably linked with implications acrossbiomedical and public health disciplines. Race is an enigma, exhibiting noclear biological definition yet strong cultural and social meanings, partieu-larl~ 10 the United States. Historically, racial groups have been classified byvanous physical attributes, such as skull volume and size, skin color, facialfeatures, and other physical atJributes. The Swedish naturalist Carl Lin-neaus's Systema Naturae (1758) defined four racial groups: Ho;"o sapienseuropaeus Ho . ... ' rna sapiens astaticus, Homo sapiens american us, and Homosfiaplensafrer. Johann Friedrich Blumenbach (1775) then provided a classi-catron of fi .. hve vaneues umans based on skin color. These racial schemapredated the mode . . .I . rn genonuc era yet are still used today when descnbmgpodPu.adtluais°nsaround the world (1,2) and are used in genetic studies to classifyill 1Vl (3).Hnwever the arri al fl· .ilia ithin- v 0 mo ecular technology led to a new realization

ad~.WI -group differences far exceeded between-group differences. Inregardles the revelation from the Human Genome Proiect that all humans,

-~~~th·· • Ishould h .e rucity, are >99% the same at the DNA sequence leveave nullified the exi .. - - -Instead. the use of . existence of biologically distinct racial groups.

eases and thgenetics to explain racial and ethnic differences in dis-

o er trans - I ifi hiloci across th 10 ens I ed. Studies using hundreds of polymorp IC

e genome have shown that groupings of individuals correlate

Chapter 4/Race and Cenecics 83

directly with ancestral continent of origin (4,5). And that the continentalclustering appears to correspond to the following division of human beings:sub-Saharan Afncans; Europeans, western Asians, and northern Africans;eastern Asians; Polynesians and other inhabitants of Oceania; and NativeAmericans (/,4). Not surprisingly, human genome research has increasinglyprojected population comparisons at the genetic level and genetic variationcontinues to be used to explain racial and ethnic group differences in health(3,6). But what are these racial groupings? Are they continental groups?How accurately do they define bounded homogeneous entities? Are the dif-ferences in health outcomes due to biological differences among the so-called "races"? Obviously, there continues to be a paradoxical relationshipbetween race and genetics.

2. HOW IS GENETIC VARIATION STRUCTURED?

Human genetic variation is structured by the history of our species. Thepattern of this structure, however, is not bounded or discrete, but continuous,resulting from the demographic history of populations shaped by forces suchas natural and social (mate) selection. Our knowledge of human genetic vari-ation has grown enormously over the past few decades. Single-nucleotidepolymorphisms (SNPs) are the most common form of DNA variation inthe human genome. At present, there are more than 10million SNPs in thehuman genome (7). A large fraction of these SNPs are found at a frequencyless than 5% and thus are private or common in only a single population (8).SNPs have been used to explore how genetic variation is structured within-and between-human populations. Gabriel et al. (9) examined 3738 SNPsacross 51 autosomal regions in sampled populations of Africans, African-Americans, Asians, and Europeans. The alleles for consecutive SNPs alonga chromosome which are inherited as a unit are called "haplotypes." Thesehaplotypes were then compared between the groups. While 51% of thehaplotypes were shared between all groups, on average, Africans (whichincluded African-Americans) possessed the most haplotypes. This findingindicates that the variation observed in European and Asian populations is asubset of African variation and furthermore supports a single African originfor all humans.Guthery et aI. (/0) arrived at similar conclusions when they examined

population structure of common genetic variants in African, European,Asian, and Hispanic American populations. At most genetic loci, Africanpopulations harbor some relatively common alleles that are absent innon-African populations; however, most of the alleles that are common innon-African populations are also common in African populations. Thus, thepattern of genetic variation is one of nested subsets, such that the vana-tion in non-African populations is a subset of the variation found in Africanpopulations. The recent out of Africa model, which postulates an African

84 2. How is Genetic Variation Structured?

origin of modern humans and subsequent migrations out into Eurasia andthe Americas best fits with this genetic data ( / /).In addition to finding the most variation within the African-American

population, Guthery et al. also noted that the genetic structure of com-mon variants within African-American populations was different than thegenetic structure of other US populations, meaning that genetic elementsinvolved in disease may differ between African-Americans and other USgroups. They attributed this difference in genetic structure to a differencein genetic ancestry between the populations. As a result, they suggest thatfuture genetic association studies consider both genetic ancestry and pop-ulation structure of the study populations. Furthermore, considering that inthe past many of the genetic association studies have included only Euro-pean populations and that those findings may not be applicable to other pop-ulations, in particular African-Americans, they suggest that future studiesshould either "oversample" African-Americans or focus on understandinghow genetic variation within African-American populations contributes todisease.Given the genetic data now available across diverse human populations,

it is becoming increasingly clear that the frequency of most genetic mark-ers do not vary much among the major continental populations. Populationgeneticists use a statistic called FST to describe the amount of total varia-tion within subpopulations relative to the total population (/2). This indexcan range from 0 to I, where 0 indicates that there is no variation betweenthe subpoputancns (little genetic differentiation) and I indicates that all thevariation is between the subpopulations (high genetic differentiation). FSTcan also be described as a measurement of genetic distance where as FSTincreases, subpopulations become more distant and/or unrelated, from eachother (/3).

Genetic variation among human groups is typically quoted as havingan FSTvaIue of O.O9--{).13 (14). This value is small compared to otherspecies With comparable geographical ranges to humans. The FST valueindicates that between 9% and 13% of the variation is between continen-tal groups while the majority of variation, 87-91 %, is within continentalgroups. ThIS observation that more variation exists within continental groupsthan between groups blurs boundaries between groups; this has been usedto argue against the biological basis to race (15,16). However, a number?f andies that eXamine genetic variation across the genome have found thatmdlV1duaIs ith . '1 .wi sum ar ancestral continental origins tend to cluster together,~. ~ 0

lU gene. ' these clusters correspond to four continental groups: Sub-~aharan Africa, EuropelWestern Asia, Asia, and the Americas (4). Addition-y, Tang et aI. (17) in 2005 showed that self-identified race/ethnicity can

~el these clusters. In spite of this, the relationship between race/ethnicityan.dgenencs remains uncertain for some. Problems regarding this issue haveanseu because the terms race and ethnicity have a multitude of definitions.

Chapter 4/Race and Genetics

In addition, the words race and ethnicity are sometimes ascribed with a neg-ative and prejudiced connotation, often associated with a particular socialhierarchy. Finally, despite the continental clustering of those with sharedancestry, there are no discrete genetic boundaries that define any race orethnicity (18).While most genetic markers have low FST levels, a small number (~5%)

have significantly higher FST than expected (8). These markers with higherthan expected FST values are within regions of the genome that many believemay have been under natural selection sometime during the history of thepopulation. The human genome should not be thought of as a single entitybut an assortment of segments which have evolved differently due to diverseenvironmental pressures. Thus, the human genome is made up of segmentswith vastly different histories.

3. MEASURE AND USE OF GENETIC ANCESTRY

Not withstanding the large amount of genetic variation shared acrosshuman groups there is a small but significant fraction of polymorph isms thatare quite informative for estimating biogeographic ancestry. Less than 5% ofpolymorphisms have large allele frequency difference between continentalpopulations (i.e., West Africans, Europeans, and Asian/Native Americans).We call these markers "ancestry informative markers" because of their highinformation content for continental or biogeographical ancestry (19).In the United Stated, variation in genetic background exists within most

self-identified racial-ethnic groups (SIRE) groups. For instance, African andHispanic Americans represent recently admixed populations with diverseancestries due to social and biological factors. Hispanic Americans are acomplex macro-ethnic group who share a common language yet can tracetheir ancestries to multiple continents (20). Interestingly, individuals self-report as African-American due to skin color and the historical classifica-tion schema referred to as the "one-drop" rule which denotes an individ-ual with an African ancestor as Black. No matter how physically "white"or "black" the person looked, he or she would be considered "Black" orAfrican-American. This racial paradigm emerged from the antebellum southand then became the nation's definition accepted by almost everyone (21).Because of this social model of one-way gene flow, the one-drop rule hasincreased the genetic heterogeneity of the African-American population inthe United States.There lacks consensus on the use of SIRE data in biomedical research

but its reliahility varies across populations (2,15). In Fig. I, we show a his-togram depicting percentage West African ancestry measured using AIMsin three SIRE populations, European Americans from State College PA;African-Americans from Washington, DC; and Hispanic Americans (PuertoRicans) living inNYc. The first striking feature observed is that 98% of the

85

,,I

-86 3. Measure and use of Generic Ancestry

1 0 European American o Puerto Ricans • African American I1.00

0.90

0.80

0.70

~ 0.600

~ 0.50<T~at: 0.40

0.30

0.20

0.10

0.0010 20 30 40 50 60 70

%West African Ancestry

Fig. 1. Frequency histogram of percentage West African genetic ancestry in individualswho self-reported as African-American, European American. and Puerto Rican.Data from (22,23).

100

European Americans had over 90% European ancestry, while only 34% ofthe African-Americans possessed over 90% West African ancestry. A broadrange nf ancestry is observed among the African and Hispanic Americanpopulations. The distribution in West African ancestry was inversely relatedbetween the two admixed populations with about 20% of the African-Americans had less than 60% West African ancestry compared to over 80%of Puerto Ricans.Contrary to some published reports self-report for African and Hispanic

Americans is not necessarily a strong proxy for genetic background. Our fig-ure highlights that differences related to geographic or continental ancestrydeconstruct traditional racial categorization. We also note that this distribu-tion is reflective only of the black/white dichotomy and does not factor inthe Native American component in these populations. The Native Americancomponent is much higber in Puerto Ricans than in European and AfricanAmerican populations due to the historical experiences of many Hispanicgroups (24).

. Variance in genetic background of study subjects is becoming more of anISSueWIththe increasing number of genetic association studies on complexdisease. Differences in genetic background among study individuals mayImpact the power and reliability of genetic association studies (25). Methodsto detect and control for differences in ancestry in genetic association studiesutilize AIMs.

Chapter 4/Race and Genetics 87

AIMs have high utility in biomedical research since they can be used toaccurately measure individual ancestry (IA) of subjects enrolled in studies.Almost all outbred populations show variation in individual ancestry whichcan introduce population stratification and impact the success of geneticstudies (26). Most importantly these IA estimates can be used to controlfor heterogeneity in genetic studies in recently admixed populations likeAfrican-Americans and Hispanic Americans. In fact, the use of AIMs tocontrol for genetic heterogeneity and population stratification in geneticsstudies is becoming widespread. AIMs were used to control for stratificationin studies of risk factors for hypertension (27), myocardial infarction (28),and asthma (29). Controlling for population stratification due to admixtureis referred to as "admixture adjustment" since ]A is used as a covariate inthe regression analyses.

4. FINDING DISEASE SUSCEPTIBILITYGENES IN ADMIXED POPULATIONS

An emerging popular approach to mapping susceptibility genes inrecently admixed populations is called admixture mapping. This novelapproach attempts to find genes that underlie ethnic differences in diseaserisk (30). Recent gene flow (admixture) between long separated populationscreates linkage disequilibrium (LD) between loci which can extend overlarge chromosomal regions (exceeding 30 cM). In this approach, we typegenome-spanning AIMs in the clinical population to infer ancestry at eachlocus and then test locus ancestry for association with the trait of interest inthe population. However, once potential regions are located using admixturemapping, conventional association tests are needed to locate the causativelocus. Admixture proportions and dynamics and marker (AIMs) character-istics all influence the power of mapping (30,31). Admixture mapping hasbeen successful for mapping disease and trait loci for multiple sclerosis (32),hypertension (33), and prostate cancer (34). However, not all diseases whichexhibit differential risk across populations are amenable to the admixturemapping approach especially when disease alleles are similar in frequencyin parental populations and disease risk is due to differences in environmen-tal and social influences. This may be the case for many disease disparitiessince they are largely influenced by social determinants.

5. HAS NATURAL SELECTION SHAPEDGENETIC VARIATION?

The extent and pattern of genetic variation in human populations havebeen influenced by natural selection. Natural selection is complex andrecent studies have produced interesting new data. Natural selection canshape genetic variation in a population by removing harmful variants,

----------------------

88 6. Conclusion

spreading favorable ones, or maintaining variation at particular genetic .loci.Has historical selection influenced the frequency of many genetic vanantsthat contribute to population differences in disease prevalence and drugresponse? If so, how much of an effect has natural selection had on shap-ins variation in genes which affect traits involved in disease pathways suchas°cardiovascular disease (CYD)? Several recent studies have utilized largegenetic datasets to search for signatures of recent selection in the humangenome (35,36). These studies indicate that genes involved in inflamma-tory response to infectious disease show a pattern of variation different fromother regions of the genome. Other categories of genes which may have beenimpacted by selective pressures include pigmentation, fertility, and repro-duction genes (35,36). Interestingly, recent work exploring gene expressiondifferences between West Africans and Europeans is consistent with the pat-tern of SNP variation within many of these genes (37).Differences in the pattern of genetic variation across human populations

can be assessed using different methods. As mentioned earlier, FST sum-marizes genetic differentiation between populations. Haplotype structureand frequency also provides some clues for potential selective events. Mosthaplotypes are shared across populations but for a subset of genes, haplo-type Structure and frequencies vary significantly across populations. Hap-lotype structure and frequencies for genes influencing physiological path-ways involved in fat storage, salt sensitivity (38), and testosterone have beenshown to vary significantly across groups. Several reasons for these patternsinclude bottleneck effects, selection, and genetic hitchhiking events.There is compelling data emerging that selection has shaped genetic

susceptibility for several common diseases (39). Recently, a number ofresearchers have shown that certain alleles that are involved in causing com-mon diseases, inclUding CVD, may have at one time conferred an evolution-ary advantage to ancestral human populations. However, with changes inmodern lifestyle, e.g., sedentism, diet, new environmental exposures, thesealleles are no longer advantageous but instead increase disease risk.Selection during the out-of-Africa expansion of human populations may

have influenced risk for hypertension (HTN) (40). Data has shown that theeffect of ancestral susceptibility alleles on risk for HTN varies across lati-tude. The hypothesis suggests that the differential susceptibility to HTN maybe d t di. ue to gra rents of exposure to selective pressures once human popula-nons migrated out of Africa about 80,000--100,000 years ago (40). Thereare clear genetic signals of selection in support of this hypothesis for severalgenes (such as AGT, CYP3A5, and GNB3) which may influence HTN andCVD (39,40).

6. CONCLUSION

Since ~ larg~ fraction of genetic variation may be localized to particulargeographic regions much attention has been focused on whether geographic

,

Chapter 4/Race and Genetics

ancestral origins contributes to the differential distribution of disease andmortality (4J). These studies continue to utilize sociopolitical constructs thatare inappropriate for investigations on genetic contributions to the etiologyof complex disease, drug response, and more importantly, health disparities.While race may be an important determinant to monitor health status andhealth-care quality (42), it lacks biological integrity. In fact, the use of raceto identify groups may confound biomedical studies. This is because racereflects deeply confounded sociocultural as well as biological factors.We suggest that ancestry be used instead of race. Genetic ancestry has

several salient features which are useful for biomedical studies. First, geneticancestry has strong utility as an index for human biological variation (J 9,26).Also when ancestry is used to describe genetic background, it allows formore sophisticated investigation of biological risk factors. Additionally,there is no historical baggage associated with genetic ancestry and it has pro-moted increased discourse between disciplines (43,44). There is an urgentneed for biomedical research to develop interdisciplinary research designsand embrace research on social determinants of health and how they influ-ence genetic risk factors. The key features of genetic ancestry also demandthat more work be done in order to better assess individual genetic ancestryand most importantly how it may be correlated with social factors such asSES and racism. Most would agree that information on genetic ancestry ispotentially more useful for efficient analyses of genetics of complex diseaseand pharmacogenetics than the traditional racial classifications.

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