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One of the major developments in recent years in the search for missingheritability of human phenotypes is the adoption of linear mixed-effects models(LMMs) to estimate heritability due to genetic variants which are notsignificantly associated with the phenotype. A variant of the LMM approach hasbeen adapted to case-control studies and applied to many major diseases by Leeet al. (2011), successfully accounting for a considerable portion of themissing heritability. For example, for Crohn's disease their estimatedheritability was 22% compared to 50-60% from family studies. In this letter wepropose to estimate heritability of disease directly by regression of phenotypesimilarities on genotype correlations, corrected to account for ascertainment.We refer to this method as genetic correlation regression (GCR). Using GCR weestimate the heritability of Crohn's disease at 34% using the same data. Wedemonstrate through extensive simulation that our method yields unbiasedheritability estimates, which are consistently higher than LMM estimates.Moreover, we develop a heuristic correction to LMM estimates, which can beapplied to published LMM results. Applying our heuristic correction increasesthe estimated heritability of multiple sclerosis from 30% to 52.6%.

Narrowing the gap on heritability of common disease by direct estimation in case-control GWAS