Next-Generation Genome-Wide Association Studies

Abstract

As investigators plan the next round of genome-wide association studies (GWAS), cohorts of more than 100 000 individuals are being proposed as the solution to the “missing heritability” from first-generation studies.1–6 Although such studies will undoubtedly reveal many additional common alleles contributing to human disease, consideration of the intrinsic design of GWAS, our knowledge of the genetic architecture of disease and the results of GWAS to date suggests that complementary strategies will be necessary to uncover all of the heritability. ### First-Generation GWAS The outcomes of GWAS to date were largely anticipated.1 By design, the approach offers an unbiased assessment of the role of common alleles in disease syndromes, and there are numerous examples of successful GWAS in which multiple loci have been unequivocally associated with specific diseases. Even in genetically heterogeneous syndromes with major mendelian contributions, shared common alleles that operate downstream to affect trait expression may be detectable.7,8 In less heritable traits, GWAS may offer the only evidence of any genetic contribution. Many of the most successful studies to date have explained only a proportion of the heritability, whereas for some key disease phenotypes no loci have been identified that achieve genome-wide statistical significance.3,7–9 Serendipitous identification of large-effect size common alleles has occurred, but these may represent common modifiers of multiple mendelian genes, genes with large interactions with environmental factors or simply very homogeneous phenotypes.10,11 Article see p 359 Although the “small effect” alleles identified in GWAS may be important at a population level, a rigorous understanding of the role of such contributions will require much more comprehensive definition the genetic architecture for each trait. Epistatic interactions among common alleles, or between common …