Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae Jennifer K. Lowe1,2,3, Julian B. Maller3,4¤a, Itsik Pe’er3,4¤b, Benjamin M. Neale3,4,5, Jacqueline Salit1, Eimear E. Kenny1, Jessica L. Shea2,3, Ralph Burkhardt1, J. Gustav Smith3, Weizhen Ji6, Martha Noel1, Jia Nee Foo 6 , Maude L. Blundell1, Vita Skilling7¤c, Laura Garcia1, Marcia L. Sullivan 1 , Heather E. Lee1, Anna Labek1, Hope Ferdowsian1, Steven B. Auerbach8, Richard P. Lifton6,9, Christopher Newton-Cheh3,4,10,11, Jan L. Breslow1, Markus Stoffel1¤d, Mark J. Daly3,4,11, David M. Altshuler 2,3,4,11*, Jeffrey M. Friedman1,9* 1 The Rockefeller University, New York, New York, United States of America, 2 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 3 Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America, 4 Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 5 Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, United Kingdom, 6 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America, 7 Kosrae Department of Health Services, Kosrae, Federated States of Micronesia, 8 Department of Health and Human Services, Heath Resources and Services Administration, New York, New York, United States of America, 9 Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America, 10 Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 11 Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America 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. Citation: Lowe JK, Maller JB, Pe’er I, Neale BM, Salit J, et al. (2009) Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae. PLoS Genet 5(2): e1000365. doi:10.1371/journal.pgen.1000365 Editor: Greg Gibson, The University of Queensland, Australia Received September 3, 2008; Accepted January 5, 2009; Published February 6, 2009 Copyright: 2009 Lowe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Starr Foundation and Howard Hughes Medical Institute. JKL was supported in part by an NIH/NIDDK grant (5R01 DK60089) and by a Massachusetts Biomedical Research Corporation Tosteson Postdoctoral Fellowship. IP was partially supported by NIH grants 1F32DK070527 and 5 U54 CA121852. RB was supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG Bu2263/1-1). Competing Interests: The authors have declared that no competing interests exist. * E-mail: altshuler@molbio.mgh.harvard.edu (DMA); friedj@rockefeller.edu (JMF) ¤a Current address: Department of Statistics, University of Oxford, Oxford, United Kingdom ¤b Current address: Department of Computer Science, Columbia University, New York, New York, United States of America ¤c Current address: Department of Health, Education, and Social Affairs, Federated States of Micronesia, Palikir, Pohnpei, Federated States of Micronesia ¤d Current address: Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland Introduction The use of isolated populations has a long history in genetic mapping, with benefits including founder effects, reduced genetic diversity, reduced genetic and environmental heterogeneity, and large, multi-generational pedigrees [1–3]. The resulting reduction in allelic heterogeneity has contributed to the success of genetic linkage and positional cloning approaches in isolated populations, particularly for the identification of Mendelian disease mutations [1]. While multiple rare mutations may segregate in an outbred population, founding events and subsequent population bottle- necks may reduce allelic diversity such that a single mutation dominates the allelic spectrum in an isolated population. In addition, previously rare mutant alleles may increase in frequency through genetic drift or natural selection, thus contributing more substantially to trait variation than in outbred populations and increasing the power of genetic mapping studies. Conceivably, the same properties that make isolated populations valuable for Mendelian trait genetics may be exploited for genome-wide association approaches to the study of complex genetic traits [3]. PLoS Genetics | www.plosgenetics.org 1 February 2009 | Volume 5 | Issue 2 | e1000365