Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae

Abstract

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.

Systematic haplotype analysis resolves a complex plasma plant sterol locus on the Micronesian Island of Kosrae

“…A full description of the screening and genotyping of the Kosraen cohort was described elsewhere (36). Briefly, we surveyed 3,148 highly related individuals from the Pacific Island of Kosrae in three separate screenings carried out in 1994, 2001, and 2003, which represent Ͼ75% of the adult population on the Island.…”

“…The levels of plasma sterols (campesterol, sitosterol, lathosterol, and total cholesterol) were measured by gas liquid chromatography, and plasma levels of campesterol, sitosterol, and lathosterol were expressed as the ratio of sterol to total plasma cholesterol levels (48). Plasma LDL-cholesterol, HDL-cholesterol, ApoA1, ApoB, and triglycerides were measured as described previously (36). IRB approval was obtained from all participating institutions.…”

“…Genome-wide SNP data were subjected to identity-by-state analyses and identity-by-descent estimation performed in PLINK (29) to correct and validate the pedigree structure. Full details of the pedigree construction are described elsewhere (36). The CraneFoot pedigree drawing software was used to visualize subsets of the extended pedigree (54).…”

“…The Pacific island of Kosrae in the Federated States of Micronesia was likely settled 2,500-1,500 years ago by individuals of Asian ancestry, and Islanders have a high incidence of obesity and diabetes (32)(33)(34)(35)(36). We focused on plasma plant sterol (PPS) levels, which were ascertained as part of a broader study to examine genetic causes Author contributions: E.E.K., A.G., J.L.B., I.P., and E.S.…”

“…of metabolic syndrome on the island (36). Plant sterols are a dietary source of neutral sterols that are structurally similar to cholesterol (37,38).…”