Interrogating local population structure for fine mapping in genome-wide association studies

Qin, Huaizhen; Morris, Nathan; Kang, Sun J.; Li, Mingyao; Tayo, Bamidele O.; Lyon, Helen N.; Hirschhorn, Joel N.; Cooper, Richard S.; Zhu, Xiaofeng

doi:10.1093/bioinformatics/btq560

Cited by 63 publications

(75 citation statements)

References 29 publications

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“…The proportion of SNPs with high |iHS| was the criterion used by Pickrell et al [9]. It has been suggested that genome-wide and locus-specific ancestries may show particular poor correlation at loci under selection compared to neutrally evolving loci [39]. We did not observe such a trend at loci with the highest iHS scores in either MEX AMR or MEX EUR .…”

Section: Methodscontrasting

confidence: 50%

Ancestral Components of Admixed Genomes in a Mexican Cohort

et al. 2011

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For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study “virtual genomes” of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and America—vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10–15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.

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Section: Methodscontrasting

confidence: 50%

Ancestral Components of Admixed Genomes in a Mexican Cohort

et al. 2011

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“…However, our simulation studies indicate that when a causal variant is an AIM and has a strong admixture mapping signal, these tests can have inflated type I error rates under the null hypothesis H 02 at the null AIM SNPs that are in admixture LD but not in background LD with the causal variant. We noticed that similar results have also been reported in [13, 14]. When evaluating the type I error rate by simulation studies, Wang et al (2011) and Qin et al (2011) used models including a covariate of local ancestry to simulate the case-control status.…”

Section: Discussionsupporting

confidence: 84%

“…To correct for the confounding effect of admixture LD in local regions and therefore map causal variants into small regions with a few hundred Kbs, association tests that adjust for local ancestries have been developed [13, 14]. However, these methods can have relatively low power in detecting causal variants with admixture mapping signals.…”

Section: Introductionmentioning

confidence: 99%

A Generalized Sequential Bonferroni Procedure for GWAS in Admixed Populations Incorporating Admixture Mapping Information into Association Tests

Ren¹,

Qin²,

Archer³

et al. 2015

Hum Hered

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Objective: To develop effective methods for GWAS in admixed populations such as African Americans. Methods: We show that, when testing the null hypothesis that the test SNP is not in background linkage disequilibrium with the causal variants, several existing methods cannot control well the family-wise error rate (FWER) in the strong sense in GWAS. These existing methods include association tests adjusting for global ancestry and joint association tests that combine statistics from admixture mapping tests and association tests that correct for local ancestry. Furthermore, we describe a generalized sequential Bonferroni (smooth-GSB) procedure for GWAS that incorporates smoothed weights calculated from admixture mapping tests into association tests that correct for local ancestry. We have applied the smooth-GSB procedure to analyses of GWAS data on American Africans from the Atherosclerosis Risk in Communities (ARIC) Study. Results: Our simulation studies indicate that the smooth-GSB procedure not only control the FWER, but also improves statistical power compared with association tests correcting for local ancestry. Conclusion: The smooth-GSB procedure can result in a better performance than several existing methods for GWAS in admixed populations.

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“…For our models, the mixing parameter α was set equal to 0.95 to accommodate linkage disequilibrium (LD), while the penalty parameter λ was selected based upon 10-fold cross-validation of the mean-squared prediction error. Age, sex, and the originally identified SNP were included as unpenalized covariates, with the previously used PCs capturing population stratification excluded from this and all further regression analyses due to the poor correlation between global and local ancestry (Qin et al 2010). SNPs were modeled under an additive genetic model and missing genotypes imputed with mean observed values.…”

Section: Methodsmentioning

confidence: 99%

Multi-ethnic analysis reveals soluble l-selectin may be post-transcriptionally regulated by 3′UTR polymorphism: the Multi-Ethnic Study of Atherosclerosis (MESA)

et al. 2015

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L-selectin is constitutively expressed on leukocytes and mediates their interaction with endothelial cells during inflammation. Previous studies on the association of soluble L-selectin (sL-selectin) with cardiovascular disease (CVD) are inconsistent. Genetic variants associated with sL-selectin levels may be a better surrogate of levels over a lifetime. We explored the association of genetic variants and sL-selectin levels in a race/ethnicity stratified random sample of 2,403 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Through a genome-wide analysis with additive linear regression models, we found that rs12938 on the SELL gene accounted for a significant portion of the protein level variance across all four races/ethnicities. To evaluate potential additional associations, elastic net models were used for variants located in the SELL/SELP/SELE genetic region and an additional two SNPs, rs3917768 and rs4987361, were associated with sL-selectin levels in African Americans. These variants accounted for a portion of protein variance that ranged from 4% in Hispanic to 14% in African Americans. To investigate the relationship of these variants with CVD, 6,317 subjects were used. No significant association was found between any of the identified SNPs and carotid intima-media thickness or presence of carotid plaque using linear and logistic regression, respectively. Similarly no significant results were found for coronary artery calcium or coronary heart disease events. In conclusion, we found that variants within the SELL gene are associated with sL-selectin levels. Despite accounting for a significant portion of the protein level variance, none of the variants was associated with clinical or subclinical CVD.

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Interrogating local population structure for fine mapping in genome-wide association studies

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 63 publications

References 29 publications

Ancestral Components of Admixed Genomes in a Mexican Cohort

Ancestral Components of Admixed Genomes in a Mexican Cohort

A Generalized Sequential Bonferroni Procedure for GWAS in Admixed Populations Incorporating Admixture Mapping Information into Association Tests

Multi-ethnic analysis reveals soluble l-selectin may be post-transcriptionally regulated by 3′UTR polymorphism: the Multi-Ethnic Study of Atherosclerosis (MESA)

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