title: 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.
authors.affiliation: The Rockefeller University, New York, New York, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.forename: Julian B
authors.initials: JB
authors.lastname: Maller
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salit
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Shea
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.forename: Weizhen
authors.initials: W
authors.lastname: Ji
authors.forename: Martha
authors.initials: M
authors.lastname: Noel
authors.forename: Jia Nee
authors.initials: JN
authors.lastname: Foo
authors.forename: Maude L
authors.initials: ML
authors.lastname: Blundell
authors.forename: Vita
authors.initials: V
authors.lastname: Skilling
authors.forename: Laura
authors.initials: L
authors.lastname: Garcia
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Sullivan
authors.forename: Heather E
authors.initials: HE
authors.lastname: Lee
authors.forename: Anna
authors.initials: A
authors.lastname: Labek
authors.forename: Hope
authors.initials: H
authors.lastname: Ferdowsian
authors.forename: Steven B
authors.initials: SB
authors.lastname: Auerbach
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Jan L
authors.initials: JL
authors.lastname: Breslow
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000483:Alleles; D018703:Founder Effect; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010139:Pacific Islands; D010375:Pedigree; D012641:Selection, Genetic; D013972:Thyrotropin / Q000235:genetics
chemical_list: D013972:Thyrotropin