Genome-wide association studies in diverse populations

Abstract

Genome-wide association (GWA) studies have identified a large number of single-nucleotide polymorphisms (SNPs) associated with disease phenotypes. As most GWA studies have been performed primarily in populations of European descent, this review examines the issues involved in extending consideration of GWA studies to diverse worldwide populations. Although challenges exist with such issues as imputation, admixture, and replication, investigation of diverse populations in GWA studies has significant potential to advance the project of mapping the genetic determinants of complex diseases for the human population as a whole.In the last few years, genome-wide association (GWA) studies have produced numerous successes in identifying genetic variants that contribute to complex human traits1 , 2. Several factors are recognized3 , 4 as having dramatically enlarged the number of genotypephenotype associations documented for a wide range of phenotypes5 , 6. These include: increasingly dense sets of genetic markers, increasingly large sample sizes, improved resources on genomic variation, and new statistical techniques for genotype imputation 7 , 8 and meta-analysis9 , 10 that leverage these resources.With few exceptions, however, GWA studies have been centered in populations of European descent (Box 1), and the degree to which knowledge gained from these studies is transferrable to other populations has not been extensively investigated. Recent reports such populations as Chinese11 , 12, Japanese13 , 14, Koreans15 , 16, and Pacific islanders from Kosrae17 , 18 represent some of the first in a new wave of GWA studies in non-European populations, as researchers seek to search additional groups for new findings on widely distributed phenotypes, to consider new phenotypes that are more prevalent in non-European populations, and to establish the generality of findings obtained initially in Europeans and European Americans. NIH Public Access Author ManuscriptNat Rev Genet. Author manuscript; available in PMC 2011 May 1. Populations in past GWA studiesTo assess the extent to which non-European populations have been incorporated into GWA studies, we examined the distribution of study populations across 492 GWA articles in the National Human Genome Research Institute catalog of GWA results6 , 130. This database provides a manually curated list of SNP-phenotype associations (P < 10 −5 ) identified in studies with at least 100,000 SNPs. Article classifications were assessed independently by two raters, with discrepancies resolved by consensus in discussions with a third rater. The figure on the right tabulates classifications based on whether articles used individuals of European descent, individuals of non-European descent, or a combination of individuals of European and non-European descent. Eight articles that provided insufficient information about study subjects are omitted, so that each bar represents 80 or 81 articles, grouped by date. The later date ranges are narrower, indicating that in more recent time periods, ...

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