The most important determinant of success in identifying associations for complex traits is the underlying genetic architecture (that is, the number of loci and their frequencies, effect sizes, modes of action and interactions with other genetic loci and environmental factors). Heritability alone reveals little about genetic architecture. In the absence of a detailed understanding of genetic architecture, sample size and phenotypic homogeneity are the critical determinants of discovering robust and replicable genetic associations. Eight genome-wide association studies (GWAS) for MDD have been published,21–28 with one locus of possible genome-wide significance. 26 When these studies were planned, there were few data to guide sample size requirements. Several had historically notable sample sizes and far more comprehensive genomic coverage than any prior study. However, it has become clear that the effects of common genetic variants for most complex human diseases are considerably smaller than many had anticipated.14 This implies that sample sizes necessary for identification of common genetic main effects were far larger than could be attained by single-research groups or existing consortia.
