Haplotypes of common SNPs can explain missing heritability of complex diseases
Gaurav Bhatia, Alexander Gusev, Po-Ru Loh, Bjarni J Vilhjálmsson, Stephan Ripke, Shaun Purcell, Eli Stahl, Mark Daly, Teresa R de Candia, Kenneth S Kendler, Michael C O’Donovan, Sang Hong Lee, Naomi R Wray, Benjamin M Neale, Matthew C Keller, Noah A Zaitlen, Bogdan Pasaniuc, Jian Yang, Alkes L Price, Schizophrenia Working Group Psychiatric Genomics C
While genome-wide significant associations generally explain only a small proportion of the narrow-sense heritability of complex disease (h2), recent work has shown that more heritability is explained by all genotyped SNPs (hg2). However, much of the heritability is still missing (hg2
0.1% explained substantially more phenotypic variance (hhap2 = 0.64 (S.E. 0.084)) than genotyped SNPs alone (hg2 = 0.32 (S.E. 0.029)). These estimates were based on cross-cohort comparisons, ensuring that cohort-specific assay artifacts did not contribute to our estimates. In a large multiple sclerosis data set (WTCCC2-MS), we observed an even larger difference between hhap2 and hg2, though data from other cohorts will be required to validate this result. Overall, our results suggest that haplotypes of common SNPs can explain a large fraction of missing heritability of complex disease, shedding light on genetic architecture and informing disease mapping strategies.