A robust and unified framework for estimating heritability in twin studies using generalized estimating equations.

The 'heritability' of a phenotype measures the proportion of trait variance due to genetic factors in a population. In the past 50 years, studies with monozygotic and dizygotic twins have estimated heritability for 17,804 traits;1 thus twin studies are popular for estimating heritability. Researchers are often interested in estimating heritability for non-normally distributed outcomes such as binary, counts, skewed or heavy-tailed continuous traits. In these settings, the traditional normal ACE model (NACE) and Falconer's method can produce poor coverage of the true heritability. Therefore, we propose a robust generalized estimating equations (GEE2) framework for estimating the heritability of non-normally distributed outcomes. The traditional NACE and Falconer's method are derived within this unified GEE2 framework, which additionally provides robust standard errors. Although the traditional Falconer's method cannot adjust for covariates, the corresponding 'GEE2-Falconer' can incorporate mean and variance-level covariate effects (e.g. let heritability vary by sex or age). Given a non-normally distributed outcome, the GEE2 models are shown to attain better coverage of the true heritability compared to traditional methods. Finally, a scenario is demonstrated where NACE produces biased estimates of heritability while Falconer remains unbiased. Therefore, we recommend GEE2-Falconer for estimating the heritability of non-normally distributed outcomes in twin studies.