Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations

Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which, cases and controls are matched by admixture, can be an appealing and a suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments. Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is a substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV(1), a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P=0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, beta(2) adrenergic receptor (beta(2)AR) and DeltaFEF(25-75), an asthma-related phenotype, as an example, we demonstrated population stratification was not a confounder in our genetic association. Our present work demonstrates that admixture-matched case-control strategies can efficiently control population stratification confounding in admixed populations.     

Exploring Population Admixture Dynamics via Empirical and Simulated Genome-wide Distribution of Ancestral Chromosomal Segments

The processes of genetic admixture determine the haplotype structure and linkage disequilibrium patterns of the admixed population, which is important for medical and evolutionary studies. However, most previous studies do not consider the inherent complexity of admixture processes. Here we proposed two approaches to explore population admixture dynamics, and we demonstrated, by analyzing genome-wide empirical and simulated data, that the approach based on the distribution of chromosomal segments of distinct ancestry (CSDAs) was more powerful than that based on the distribution of individual ancestry proportions. Analysis of 1,890 African Americans showed that a continuous gene flow model, in which the African American population continuously received gene flow from European populations over about 14 generations, best explained the admixture dynamics of African Americans among several putative models. Interestingly, we observed that some African Americans had much more European ancestry than the simulated samples, indicating substructures of local ancestries in African Americans that could have been caused by individuals from some particular lineages having repeatedly admixed with people of European ancestry. In contrast, the admixture dynamics of Mexicans could be explained by a gradual admixture model in which the Mexican population continuously received gene flow from both European and Amerindian populations over about 24 generations. Our results also indicated that recent gene flows from Sub-Saharan Africans have contributed to the gene pool of Middle Eastern populations such as Mozabite, Bedouin, and Palestinian. In summary, this study not only provides approaches to explore population admixture dynamics, but also advances our understanding on population history of African Americans, Mexicans, and Middle Eastern populations.     

Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study

U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.     

A general population-genetic model for the production by population structure of spurious genotype-phenotype associations in discrete, admixed or spatially distributed populations

In linkage disequilibrium mapping of genetic variants causally associated with phenotypes, spurious associations can potentially be generated by any of a variety of types of population structure. However, mathematical theory of the production of spurious associations has largely been restricted to population structure models that involve the sampling of individuals from a collection of discrete subpopulations. Here, we introduce a general model of spurious association in structured populations, appropriate whether the population structure involves discrete groups, admixture among such groups, or continuous variation across space. Under the assumptions of the model, we find that a single common principle--applicable to both the discrete and admixed settings as well as to spatial populations--gives a necessary and sufficient condition for the occurrence of spurious associations. Using a mathematical connection between the discrete and admixed cases, we show that in admixed populations, spurious associations are less severe than in corresponding mixtures of discrete subpopulations, especially when the variance of admixture across individuals is small. This observation, together with the results of simulations that examine the relative influences of various model parameters, has important implications for the design and analysis of genetic association studies in structured populations.     

Design and analysis of admixture mapping studies

Admixture between populations originating on different continents can be exploited to detect disease susceptibility loci at which risk alleles are distributed differentially between these populations. We first examine the statistical power and mapping resolution of this approach in the limiting situation in which gamete admixture and locus ancestry are measured without uncertainty. We show that, for a rare disease, the most efficient design is to study affected individuals only. In a typical African American population (two-way admixture proportions 0.8/0.2, ancestry crossover rate 2 per 100 cM), a study of 800 affected individuals has 90% power to detect at P values <10(-5) a locus that generates a risk ratio of 2 between populations, with an expected mapping resolution (size of 95% confidence region for the position of the locus) of 4 cM. In practice, to infer locus ancestry from marker data requires Bayesian computationally intensive methods, as implemented in the program ADMIXMAP. Affected-only study designs require strong prior information on the frequencies of each allele given locus ancestry. We show how data from unadmixed and admixed populations can be combined to estimate these ancestry-specific allele frequencies within the admixed population under study, allowing for variation between allele frequencies in unadmixed and admixed populations. Using simulated data based on the genetic structure of the African American population, we show that 60% of information can be extracted in a test for linkage using markers with an ancestry information content of 36% at 3-cM spacing. As in classic linkage studies, the most efficient strategy is to use markers at a moderate density for an initial genome search and then to saturate regions of putative linkage with additional markers, to extract nearly all information about locus ancestry.     

Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil

Admixed populations have not been examined in detail in cancer genetic studies. Here, we inferred the local ancestry of cancer-associated single nucleotide polymorphisms (SNPs) and haplotypes of a highly admixed Brazilian population. SNP array was used to genotype 73 unrelated individuals aged 80-102 years. Local ancestry inference was performed by merging genotyped regions with phase three data from the 1000 Genomes Project Consortium using RFmix. The average ancestry tract length was 9.12-81.71 megabases. Strong linkage disequilibrium was detected in 48 haplotypes containing 35 SNPs in 10 cancer driver genes. All together, 19 risk and eight protective alleles were identified in 23 out of 48 haplotypes. Homozygous individuals were mainly of European ancestry, whereas heterozygotes had at least one Native American and one African ancestry tract. Native-American ancestry for homozygous individuals with risk alleles for HNF1B, CDH1, and BRCA1 was inferred for the first time. Results indicated that analysis of SNP polymorphism in the present admixed population has a high potential to identify new ancestry-associated alleles and haplotypes that modify cancer susceptibility differentially in distinct human populations. Future case-control studies with populations with a complex history of admixture could help elucidate ancestry-associated biological differences in cancer incidence and therapeutic outcomes.     

A Genomic Portrait of Haplotype Diversity and Signatures of Selection in Indigenous Southern African Populations

We report a study of genome-wide, dense SNP (∼900K) and copy number polymorphism data of indigenous southern Africans. We demonstrate the genetic contribution to southern and eastern African populations, which involved admixture between indigenous San, Niger-Congo-speaking and populations of Eurasian ancestry. This finding illustrates the need to account for stratification in genome-wide association studies, and that admixture mapping would likely be a successful approach in these populations. We developed a strategy to detect the signature of selection prior to and following putative admixture events. Several genomic regions show an unusual excess of Niger-Kordofanian, and unusual deficiency of both San and Eurasian ancestry, which were considered the footprints of selection after population admixture. Several SNPs with strong allele frequency differences were observed predominantly between the admixed indigenous southern African populations, and their ancestral Eurasian populations. Interestingly, many candidate genes, which were identified within the genomic regions showing signals for selection, were associated with southern African-specific high-risk, mostly communicable diseases, such as malaria, influenza, tuberculosis, and human immunodeficiency virus/AIDs. This observation suggests a potentially important role that these genes might have played in adapting to the environment. Additionally, our analyses of haplotype structure, linkage disequilibrium, recombination, copy number variation and genome-wide admixture highlight, and support the unique position of San relative to both African and non-African populations. This study contributes to a better understanding of population ancestry and selection in south-eastern African populations; and the data and results obtained will support research into the genetic contributions to infectious as well as non-communicable diseases in the region.     

The Admixture Structure and Genetic Variation of the Archipelago of Cape Verde and Its Implications for Admixture Mapping Studies

Recently admixed populations offer unique opportunities for studying human history and for elucidating the genetic basis of complex traits that differ in prevalence between human populations. Historical records, classical protein markers, and preliminary genetic data indicate that the Cape Verde islands in West Africa are highly admixed and primarily descended from European males and African females. However, little is known about the variation in admixture levels, admixture dynamics and genetic diversity across the islands, or about the potential of Cape Verde for admixture mapping studies. We have performed a detailed analysis of phenotypic and genetic variation in Cape Verde based on objective skin color measurements, socio-economic status (SES) evaluations and data for 50 autosomal, 34 X-chromosome, and 21 non-recombinant Y-chromosome (NRY) markers in 845 individuals from six islands of the archipelago. We find extensive genetic admixture between European and African ancestral populations (mean West African ancestry = 0.57, sd = 0.08), with individual African ancestry proportions varying considerably among the islands. African ancestry proportions calculated with X and Y-chromosome markers confirm that the pattern of admixture has been sex-biased. The high-resolution NRY-STRs reveal additional patterns of variation among the islands that are most consistent with differentiation after admixture. The differences in the autosomal admixture proportions are clearly evident in the skin color distribution across the islands (Pearson r = 0.54, P-value<2e–16). Despite this strong correlation, there are significant interactions between SES and skin color that are independent of the relationship between skin color and genetic ancestry. The observed distributions of admixture, genetic variation and skin color and the relationship of skin color with SES relate to historical and social events taking place during the settlement history of Cape Verde, and have implications for the design of association studies using this population.     

Dissecting linkage disequilibrium in African-American genomes: roles of markers and individuals

Substantial increases of linkage disequilibrium (LD) both in magnitude and in range have been observed in recently admixed populations such as African-American (AfA). On the other hand, it has also been shown that LD in AfAs was very similar to that of African. In this study, we attempted to resolve these contradicting observations by conducting a systematic examination of the LD structure in AfAs by genotyping a sample of AfA individuals at 24,341 single nucleotide polymorphisms (SNPs) spanning almost the entire chromosome 21, with an average density of 1.5 kb/SNP. The overall LD in AfAs is similar to that in African populations and much less than that in European populations. Even when the ancestry-informative markers (AIMs) were used, extended LD in AfA was found to be limited to certain magnitude range (0.2 < or = r(2) < or = 0.8) and certain distance range, that is, between-marker distance more than 200 kb. Furthermore, the inclusion of AfA individuals with predominant African ancestry was found to reduce the overall magnitude of LD. Elevation of LD in the AfA population, compared with its parental populations, can only be observed at the markers with large allele frequency differences between 2 parental populations at limited scenario. AfA individuals of wholly African ancestry contribute little to the extended LD in the AfA population, and further genotyping or association analysis conducted using only admixed individuals may lead to higher statistical power and possibly reduced cost.     

Ethnic-difference markers for use in mapping by admixture linkage disequilibrium

Mapping by admixture linkage disequilibrium (MALD) is a potentially powerful technique for the mapping of complex genetic diseases. The practical requirements of this method include (a) a set of markers spanning the genome that have large allele-frequency differences between the parental ethnicities contributing to the admixed population and (b) an understanding of the extent of admixture in the study population. To this end, a DNA-pooling technique was used to screen microsatellite and diallelic insertion/deletion markers for allele-frequency differences between putative representatives of the parental populations of the admixed Mexican American (MA) and African American (AA) populations. Markers with promising pooled differences were then confirmed by individual genotyping in both the parental and admixed populations. For the MA population, screening of >600 markers identified 151 ethnic-difference markers (EDMs) with delta>0.30 (where delta is the absolute value of each allele-frequency difference between two populations, summed over all marker alleles and divided by two) that are likely to be useful for MALD analysis. For the AA population, analysis of >400 markers identified 97 EDMs. In addition, individual genotyping of these markers in Pima Amerindians, Yavapai Amerindians, European American (EA) individuals, Africans from Zimbabwe, MA individuals, and AA individuals, as well as comparison to the CEPH genotyping set, suggests that the differences between subpopulations of an ethnicity are small for many markers with large interethnic differences. Estimates of admixture that are based on individual genotyping of these markers are consistent with a 60% EA:40% Amerindian contribution to MA populations and with a 20% EA:80% African contribution to AA populations. Taken together, these data suggest that EDMs with large interpopulation and small intrapopulation differences can be readily identified for MALD studies in both AA and MA populations.     

A Panel of Ancestry Informative Markers for the Complex Five-Way Admixed South African Coloured Population

Admixture is a well known confounder in genetic association studies. If genome-wide data is not available, as would be the case for candidate gene studies, ancestry informative markers (AIMs) are required in order to adjust for admixture. The predominant population group in the Western Cape, South Africa, is the admixed group known as the South African Coloured (SAC). A small set of AIMs that is optimized to distinguish between the five source populations of this population (African San, African non-San, European, South Asian, and East Asian) will enable researchers to cost-effectively reduce false-positive findings resulting from ignoring admixture in genetic association studies of the population. Using genome-wide data to find SNPs with large allele frequency differences between the source populations of the SAC, as quantified by Rosenberg et. al''s -statistic, we developed a panel of AIMs by experimenting with various selection strategies. Subsets of different sizes were evaluated by measuring the correlation between ancestry proportions estimated by each AIM subset with ancestry proportions estimated using genome-wide data. We show that a panel of 96 AIMs can be used to assess ancestry proportions and to adjust for the confounding effect of the complex five-way admixture that occurred in the South African Coloured population.     

Recent admixture in an Indian population of African ancestry

Identification and study of genetic variation in recently admixed populations not only provides insight into historical population events but also is a powerful approach for mapping disease loci. We studied a population (OG-W-IP) that is of African-Indian origin and has resided in the western part of India for 500 years; members of this population are believed to be descendants of the Bantu-speaking population of Africa. We have carried out this study by using a set of 18,534 autosomal markers common between Indian, CEPH-HGDP, and HapMap populations. Principal-components analysis clearly revealed that the African-Indian population derives its ancestry from Bantu-speaking west-African as well as Indo-European-speaking north and northwest Indian population(s). STRUCTURE and ADMIXTURE analyses show that, overall, the OG-W-IPs derive 58.7% of their genomic ancestry from their African past and have very little inter-individual ancestry variation (8.4%). The extent of linkage disequilibrium also reveals that the admixture event has been recent. Functional annotation of genes encompassing the ancestry-informative markers that are closer in allele frequency to the Indian ancestral population revealed significant enrichment of biological processes, such as ion-channel activity, and cadherins. We briefly examine the implications of determining the genetic diversity of this population, which could provide opportunities for studies involving admixture mapping.     

A genomewide admixture mapping panel for Hispanic/Latino populations

Admixture mapping (AM) is a promising method for the identification of genetic risk factors for complex traits and diseases showing prevalence differences among populations. Efficient application of this method requires the use of a genomewide panel of ancestry-informative markers (AIMs) to infer the population of origin of chromosomal regions in admixed individuals. Genomewide AM panels with markers showing high frequency differences between West African and European populations are already available for disease-gene discovery in African Americans. However, no such a map is yet available for Hispanic/Latino populations, which are the result of two-way admixture between Native American and European populations or of three-way admixture of Native American, European, and West African populations. Here, we report a genomewide AM panel with 2,120 AIMs showing high frequency differences between Native American and European populations. The average intermarker genetic distance is ~1.7 cM. The panel was identified by genotyping, with the Affymetrix GeneChip Human Mapping 500K array, a population sample with European ancestry, a Mesoamerican sample comprising Maya and Nahua from Mexico, and a South American sample comprising Aymara/Quechua from Bolivia and Quechua from Peru. The main criteria for marker selection were both high information content for Native American/European ancestry (measured as the standardized variance of the allele frequencies, also known as "f value") and small frequency differences between the Mesoamerican and South American samples. This genomewide AM panel will make it possible to apply AM approaches in many admixed populations throughout the Americas.     

Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.     

Skin pigmentation,biogeographical ancestry and admixture mapping

Ancestry informative markers (AIMs) are genetic loci showing alleles with large frequency differences between populations. AIMs can be used to estimate biogeographical ancestry at the level of the population, subgroup (e.g. cases and controls) and individual. Ancestry estimates at both the subgroup and individual level can be directly instructive regarding the genetics of the phenotypes that differ qualitatively or in frequency between populations. These estimates can provide a compelling foundation for the use of admixture mapping (AM) methods to identify the genes underlying these traits. We present details of a panel of 34 AIMs and demonstrate how such studies can proceed, by using skin pigmentation as a model phenotype. We have genotyped these markers in two population samples with primarily African ancestry, viz. African Americans from Washington D.C. and an African Caribbean sample from Britain, and in a sample of European Americans from Pennsylvania. In the two African population samples, we observed significant correlations between estimates of individual ancestry and skin pigmentation as measured by reflectometry (R(2)=0.21, P<0.0001 for the African-American sample and R(2)=0.16, P<0.0001 for the British African-Caribbean sample). These correlations confirm the validity of the ancestry estimates and also indicate the high level of population structure related to admixture, a level that characterizes these populations and that is detectable by using other tests to identify genetic structure. We have also applied two methods of admixture mapping to test for the effects of three candidate genes (TYR, OCA2, MC1R) on pigmentation. We show that TYR and OCA2 have measurable effects on skin pigmentation differences between the west African and west European parental populations. This work indicates that it is possible to estimate the individual ancestry of a person based on DNA analysis with a reasonable number of well-defined genetic markers. The implications and applications of ancestry estimates in biomedical research are discussed.     

Multiple Loci Associated with Renal Function in African Americans

The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in APOL1 associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry vs. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans.     

Estimating African American admixture proportions by use of population-specific alleles.

We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.     

Geographic patterns of genome admixture in Latin American Mestizos

The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region.     

Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.     

Comparing genetic ancestry and self-reported race/ethnicity in a multiethnic population in New York City

Self-reported race/ethnicity is frequently used in epidemiological studies to assess an individual’s background origin. However, in admixed populations such as Hispanic, self-reported race/ethnicity may not accurately represent them genetically because they are admixed with European, African and Native American ancestry. We estimated the proportions of genetic admixture in an ethnically diverse population of 396 mothers and 188 of their children with 35 ancestry informative markers (AIMs) using the STRUCTURE version 2.2 program. The majority of the markers showed significant deviation from Hardy-Weinberg equilibrium in our study population. In mothers self-identified as Black and White, the imputed ancestry proportions were 77.6% African and 75.1% European respectively, while the racial composition among self-identified Hispanics was 29.2% European, 26.0% African, and 44.8% Native American. We also investigated the utility of AIMs by showing the improved fitness of models in paraoxanase-1 genotype-phenotype associations after incorporating AIMs; however, the improvement was moderate at best. In summary, a minimal set of 35 AIMs is sufficient to detect population stratification and estimate the proportion of individual genetic admixture; however, the utility of these markers remains questionable.