Discerning the Ancestry of European Americans in Genetic Association Studies

Price, Alkes L.; Butler, Johannah L.; Patterson, Nick; Capelli, Cristian; Pascali, Vincenzo Lorenzo; Scarnicci, Francesca; Ruiz-Linares, Andrés; Groop, Leif; Saetta, Angelica A.; Korkolopoulou, Penelope; Seligsohn, Uri; Waliszewska, Alicja; Schirmer, Christine; Ardlie, Kristin; Ramos, Alexis; Nemesh, James; Arbeitman, Lori; Goldstein, David B.; Reich, David; Hirschhorn, Joel N.

doi:10.1371/journal.pgen.0030236

Cited by 281 publications

(256 citation statements)

References 33 publications

(60 reference statements)

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“…34,44,45 We extend these observations by showing that a local European-American population is already subtly distinct from its European sources. We found that European Americans exhibit visibly greater dispersion along higher-order PCs than Europeans (Figure 2b and Supplementary Figures S5 and S6) despite marginal values of F ST (Table 2) and continued coincidence between the groups along top PCs (Figure 2a and Supplementary Figure S4).…”

Section: Similarity and Divergence Between Central Wisconsin And Europesupporting

confidence: 54%

Genetic ancestry inference using support vector machines, and the active emergence of a unique American population

2012

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We use genotype data from the Marshfield Clinical Research Foundation Personalized Medicine Research Project to investigate genetic similarity and divergence between Europeans and the sampled population of European Americans in Central Wisconsin, USA. To infer recent genetic ancestry of the sampled Wisconsinites, we train support vector machines (SVMs) on the positions of Europeans along top principal components (PCs). Our SVM models partition continent-wide European genetic variance into eight regional classes, which is an improvement over the geographically broader categories of recent ancestry reported by personal genomics companies. After correcting for misclassification error associated with the SVMs (o10%, in all cases), we observe a 414% discrepancy between insular ancestries reported by Wisconsinites and those inferred by SVM. Values of F ST as well as Mantel tests for correlation between genetic and European geographic distances indicate minimal divergence between Europe and the local Wisconsin population. However, we find that individuals from the Wisconsin sample show greater dispersion along higher-order PCs than individuals from Europe. Hypothesizing that this pattern is characteristic of nascent divergence, we run computer simulations that mimic the recent peopling of Wisconsin. Simulations corroborate the pattern in higher-order PCs, demonstrate its transient nature, and show that admixture accelerates the rate of divergence between the admixed population and its parental sources relative to drift alone. Together, empirical and simulation results suggest that genetic divergence between European source populations and European Americans in Central Wisconsin is subtle but already under way.

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Section: Similarity and Divergence Between Central Wisconsin And Europesupporting

confidence: 54%

Genetic ancestry inference using support vector machines, and the active emergence of a unique American population

2012

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“…We propose two applications 5,26 for this AIMs panel: (1) to evaluate study design before starting GWAS, for example, by genotyping cases and controls on this panel, we can remove unsuitable cases and controls; (2) to be used for genotyping in targeted association studies, such as CGAS or replication studies following GWAS, in which variants are targeted in a large number of samples that have not been densely genotyped. Our AIMs panel can be used to efficiently correct for stratification using methods such as EIGENSTRAT not genomic control procedure, to ensure that the observed associations are not spurious without relying on self-reported ancestry.…”

Section: Discussionmentioning

confidence: 99%

“…To discern the ancestry of Europeans or European Americans, multiple sets of AIMs have been established that allow correction for population stratification in association studies using Europeans. [5][6][7] Recently, a great number of genetic association studies on various diseases have been conducted on non-European populations.…”

Section: Introductionmentioning

confidence: 99%

A panel of ancestry informative markers to estimate and correct potential effects of population stratification in Han Chinese

Qin

Jin

et al. 2013

Eur J Hum Genet

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Population stratification acts as a confounding factor in genetic association studies and may lead to false-positive or falsenegative results. Previous studies have analyzed the genetic substructures in Han Chinese population, the largest ethnic group in the world comprising B20% of the global human population. In this study, we examined 5540 Han Chinese individuals with about 1 million single-nucleotide polymorphisms (SNPs) and screened a panel of ancestry informative markers (AIMs) to facilitate the discerning and controlling of population structure in future association studies on Han Chinese. Based on genomewide data, we first confirmed our previous observation of the north-south differentiation in Han Chinese population. Second, we developed a panel of 150 validated SNP AIMs to determine the northern or southern origin of each Han Chinese individual. We further evaluated the performance of our AIMs panel in association studies in simulation analysis. Our results showed that this AIMs panel had sufficient power to discern and control population stratification in Han Chinese, which could significantly reduce false-positive rates in both genome-wide association studies (GWAS) and candidate gene association studies (CGAS). We suggest this AIMs panel be genotyped and used to control and correct population stratification in the study design or data analysis of future association studies, especially in CGAS which is the most popular approach to validate previous reports on genetic associations of diseases in post-GWAS era.

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“…Contemporary Jewish communities have been genetically analyzed both from population genetics and medical perspectives by means of uniparental and recombining markers, [10][11][12][13][14][15][16][17] and more recently also through genome-wide approaches. [18][19][20][21][22][23] However, only a few reports have been published on Sephardic and crypto-Jewish descendants.…”

Section: Introductionmentioning

confidence: 99%

Echoes from Sepharad: signatures on the maternal gene pool of crypto-Jewish descendants

et al. 2014

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The majority of genetic studies on Jewish populations have been focused on Ashkenazim, and genetic data from the Sephardic original source, the Iberian Peninsula, are particularly scarce. Regarding the mitochondrial genome, the available information is limited to a single Portuguese village, Belmonte, where just two different lineages (a single one corresponding to 93.3%) were found in 30 individuals. Aiming at disclosing the ancestral maternal background of the Portuguese Jewry, we enlarged the sampling to other crypto-Jewish descendants in the Braganc¸a district (NE Portugal). Fifty-seven complete mtDNA genomes were newly sequenced and -in contrast with Belmonte -a high level of diversity was found, with five haplogroups (HV0b, N1, T2b11, T2e and U2e) being putatively identified as Sephardic founding lineages. Therefore -in sharp contrast with Belmonte -these communities have managed to escape the expected inbreeding effects caused by centuries of religious repression and have kept a significant proportion of the Sephardic founder gene pool. This deeper analysis of the surviving Sephardic maternal lineages allowed a much more comprehensive and detailed perspective on the origins and survival of the Sephardic genetic heritage. In line with previously published results on Sephardic paternal lineages, our findings also show a surprising resistance to the erosion of genetic diversity in the maternal lineages.

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Discerning the Ancestry of European Americans in Genetic Association Studies

Cited by 281 publications

References 33 publications

Genetic ancestry inference using support vector machines, and the active emergence of a unique American population

Genetic ancestry inference using support vector machines, and the active emergence of a unique American population

A panel of ancestry informative markers to estimate and correct potential effects of population stratification in Han Chinese

Echoes from Sepharad: signatures on the maternal gene pool of crypto-Jewish descendants

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