Evaluating potential for whole-genome studies in Kosrae, an isolated population in Micronesia

Whole-genome association studies are predicted to be especially powerful in isolated populations owing to increased linkage disequilibrium (LD) and decreased allelic diversity, but this possibility has not been empirically tested 1–3 .W e compared genome-wide data on 113,240 SNPs typed on 30 trios from the Pacific island of Kosrae to the same markers typed in the 270 samples from the International HapMap Project 4,5 . The extent of LD is longer and haplotype diversity is lower in Kosrae than in the HapMap populations. More than 98% of Kosraen haplotypes are present in HapMap populations, indicating that HapMap will be useful for genetic studies on Kosrae. The long-range LD around common alleles and limited diversity result in improved efficiency in genetic studies in this population and augments the power to detect association of ‘hidden SNPs’. The use of LD-based mapping strategies makes it practical to perform whole-genome association studies without typing every common variant in the human genome 6,7 . It has been suggested that the power of such studies is increased in isolated populations, and this has been demonstrated for rare alleles 8 . However, it remains unclear whether LD among common alleles in isolated populations extends significantly farther than in other populations—far enough to have impact for studies that seek to identify alleles contributing to common complex traits 9‐11 . Thus, although LD has been observed around rare alleles (such as disease genes) in isolated populations, facilitating disease gene mapping and cloning, this finding has not been extended to the common alleles and haplotypes that are the focus of the HapMap project. Even among isolated populations, variation in demographic history has powerful consequences for LD structure around rare alleles 3,12,13 , necessitating an evaluation of each population to assess the power of an LD-based mapping strategy. Thus, with the intense worldwide effort to generate a haplotype map for the general population, it is important to establish the utility of marker sets developed using samples from the HapMap project for use in other populations. We addressed these issues using samples from the island of Kosrae, Federated States of Micronesia 14 , which was settled by a small number of Micronesian founders B2,000 years ago 15 . In the current study, we generated a genome-wide high-density dataset of B110,000 SNPs to assess the effects of Kosraen population history on genomic variation in 30 Kosraen (KOS) trios. These same SNPs have been typed in the samples used in the HapMap project (see Methods). The 30 Kosraen trios were chosen such that all trios would be five or more generations separated from each other, which represents the most distant branches of the Kosrae pedigree. Thus, the individuals in these trios allow a fuller sampling of the range of diversity on Kosrae than if we had analyzed a random set of individuals. Comparing data on the same set of markers typed in samples included in the HapMap project permits examination of the relative extent of LD and haplotype diversity in Kosrae compared with these other populations.