It is also possible that heterogeneity contributes to the discrepancy between the heritability estimates of complex diseases and the proportion of phenotypic variance explained by the identified loci in genome-wide association studies (GWAS). Indeed, the estimated effect sizes of genetic associations in GWAS of complex traits are significantly reduced by imprecise phenotyping [11], [12]. This discrepancy appears to be of larger magnitude in psychiatric disorders than in other complex traits [13]. For instance, the heritability of BD has been estimated to be as high as 85% [14], [15]. But only a smaller fraction of BD heritability is accounted for by loci identified through GWAS, even when considering all GWAS polymorphisms simultaneously [16]–[19].
