The LoF-intolerant genes and the six conditionally independent (‘significant’) CNS-related gene sets together account for 39% of schizophrenia SNP-based heritability (P = 5.07 × 10−26), equating to 61% of genic heritability (Fig. 2a and Supplementary Table 7). This is likely to be an underestimation of the true effect of these gene sets, as distal non-genic regulatory elements (not included in this analysis) will add to the heritability explained by these genes. In examining the relationship between the LoF-intolerant and CNS-related gene sets (Fig. 2a), genes belonging to both categories were the most highly enriched (2.6-fold, P = 7.90 × 10−15), although LoF-intolerant genes that were not annotated to our significant CNS gene sets still displayed enrichment for SNP-based heritability (1.74-fold, P = 9.77 × 10−10), while genes that were in the significant CNS gene sets but had pLI <0.9 showed more modest enrichment (1.39-fold, P = 6.05 × 10−4). Notably, genes outside these categories were depleted in heritability relative to their SNP content (enrichment = 0.79, P = 1.82 × 10−7).
