Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.
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.
Lowe
Jennifer K
JK
The Rockefeller University, New York, New York, USA.
Maller
Julian B
JB
Pe'er
Itsik
I
Neale
Benjamin M
BM
Salit
Jacqueline
J
Kenny
Eimear E
EE
Shea
Jessica L
JL
Burkhardt
Ralph
R
Smith
J Gustav
JG
Ji
Weizhen
W
Noel
Martha
M
Foo
Jia Nee
JN
Blundell
Maude L
ML
Skilling
Vita
V
Garcia
Laura
L
Sullivan
Marcia L
ML
Lee
Heather E
HE
Labek
Anna
A
Ferdowsian
Hope
H
Auerbach
Steven B
SB
Lifton
Richard P
RP
Newton-Cheh
Christopher
C
Breslow
Jan L
JL
Stoffel
Markus
M
Daly
Mark J
MJ
Altshuler
David M
DM
Friedman
Jeffrey M
JM
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
D013972:Thyrotropin