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Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies.

ABSTRACT: European-ancestry populations are recognized as stratified but not as admixed, implying that residual confounding by locus-specific ancestry can affect studies of association, polygenic adaptation, and polygenic risk scores. We integrate individual-level genome-wide data from ~19,000 European-ancestry individuals across 79 European populations and five European American cohorts. We generate a new reference panel that captures ancestral diversity missed by both the 1000 Genomes and Human Genome Diversity Projects. Both Europeans and European Americans are admixed at the subcontinental level, with admixture dates differing among subgroups of European Americans. After adjustment for both genome-wide and locus-specific ancestry, associations between a highly differentiated variant in LCT (rs4988235) and height or LDL-cholesterol were confirmed to be false positives whereas the association between LCT and body mass index was genuine. We provide formal evidence of subcontinental admixture in individuals with European ancestry, which, if not properly accounted for, can produce spurious results in genetic epidemiology studies.

SUBMITTER: Gouveia MH

PROVIDER: S-EPMC10630423 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies.

Gouveia Mateus H MH Bentley Amy R AR Leal Thiago P TP Tarazona-Santos Eduardo E Bustamante Carlos D CD Adeyemo Adebowale A AA Rotimi Charles N CN Shriner Daniel D

Nature communications 20231107 1

European-ancestry populations are recognized as stratified but not as admixed, implying that residual confounding by locus-specific ancestry can affect studies of association, polygenic adaptation, and polygenic risk scores. We integrate individual-level genome-wide data from ~19,000 European-ancestry individuals across 79 European populations and five European American cohorts. We generate a new reference panel that captures ancestral diversity missed by both the 1000 Genomes and Human Genome D ...[more]

PMID: 37935687

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Project description: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.

Project description:Systemic Lupus Erythematosus (SLE) disproportionately affects minorities, such as Hispanic Americans (HA). Prevalence of SLE is 3-5 times higher in HA than in European-derived populations and have more active disease at the time of diagnosis, with more serious organ system involvement. HA is an admixed population, it is possible that there is an effect of admixture on the relative risk of the disease. This admixture can create substantial increase of linkage disequilibrium (LD) in both magnitude and range, which can provide a unique opportunity for admixture mapping. The main objectives of this study are to (a) estimate hidden population structure in HA individuals; (b) estimate individual ancestry proportions and its impact on SLE risk; (c) assess impact of admixture on ITGAM association, a recently identified SLE susceptibility gene; and (d) estimate power of admixture mapping in HA. Our dataset contained 1125 individuals, of whom 884 (657 SLE cases and 227 controls) were self-classified as HA. Using 107 unlinked ancestry informative markers (AIMs), we estimated hidden population structure and individual ancestry in HA. Out of 5671 possible pairwise LD, 54% were statistically significant, indicating recent population admixture. The best-fitted model for HA was a four-population model with average ancestry of European (48%), American-Indian (AI) (40%), African (8%) and a fourth population (4%) with unknown ancestry. We also identified significant higher risk associated with AI ancestry (odds ratio (OR)=4.84, P=0.0001, 95% CI (confidence interval)=2.14-10.95) on overall SLE. We showed that ITGAM is associated as a risk factor for SLE (OR=2.06, P=8.74 x 10(-5), 95% CI=1.44-2.97). This association is not affected by population substructure or admixture. We have shown that HA have great potential and are an appropriate population for admixture mapping. As expected, the case-only design is more powerful than case-control design, for any given admixture proportion or ancestry risk ratio.

Dataset Information

Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies.

Publications

Unappreciated subcontinental admixture in Europeans and European Americans and implications for genetic epidemiology studies.

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