Mega-analysis quantifies ‘hidden heritability’ due to heterogeneity
Mills MC., Tropf FC., Lee SH., Verweij RM., Stulp G., van der Moost PJ., de Vlaming R., Bakshi A., Briley DA., Rahal C., Hellpap R., Nyman A., Esko T., Metspalu A., Medland SE., Martin NG., Barban N., Snieder H., Robinson MR.
The genome-wide association studies (GWAS) dominating genetic discovery are based on large meta-analyses that combine data from diverse historical time periods and populations. Polygenic scores constructed from GWAS explain only a fraction of the heritability derived from twin and whole-genome studies on single-populations, known as the ‘hidden heritability’ puzzle. Using seven sampling populations (N=35,062), we test whether hidden heritability is attributed to genetic heterogeneity, showing that estimates are substantially and generally smaller from across compared to within populations. We show that the hidden SNP-based heritability ranges from zero (height), 20% (BMI), 37% (education), 40% (age at first birth) to 75% (number of children). Simulations demonstrate that our results more likely reflect heterogeneity in phenotypic measurement or gene-environment interaction than genetic explanations. These findings have substantial implications for gene discovery, suggesting that large homogenous datasets are required for behavioural phenotypes and that gene-environment interaction is a central challenge for genetic discovery.