A primary question is whether heritability associates with gene sets, pathways, or quantitative gene features, which we generically refer to as heritability enrichment. We employed DAVID/EASE as a descriptive tool to investigate heritable genes clusters. 35 However, simple methods that ignore transcriptomic correlation produce very high false positive rates. 53 Furthermore, a large number of genes are heritable, necessitating “competitive” enrichment testing, 87 contrasting heritability of each set of genes with the complementary set. Accordingly, we devised a rigorous testing approach for each gene set. We used a covariate-residualized version of the expression data, computing the ICC-based estimate for complete twin pairs as h2 = 2(ρ̂MZ − ρ̂DZ) for all genes using the best-h2 transcripts. For the observed data, this approach was highly consistent with the REML estimates (r=0.992, Supplementary Note). Twin zygosity status was permuted 1,000 times, and for each permutation h2 was computed for all genes, along with the difference in mean h2 for the gene set versus the complementary set. As this difference is nearly normally distributed, an enrichment z-statistic was calculated as the observed difference divided
