Our finding that LoF-intolerant genes are enriched for common risk variants raises the question of how such alleles are found at common frequencies in the population. While the contribution of ultra-rare variation in functionally important genes to disorders associated with low fecundity can be accounted for by de novo mutation16,19,27, this cannot explain the persistence of common alleles. To address this question, we used partitioned LDSR to test the relationship between schizophrenia-associated alleles and SNP-based signatures of natural selection. These included measures of positive selection, background selection and Neanderthal introgression. We examined the heritability of SNPs after thresholding them at extreme values for these metrics (top 2%, 1% and 0.5%), including in the baseline model annotation sets such as LoF-intolerant genes and genomic regions with extreme LD patterns (Methods).
