Given that mutation intolerance is due to high selection pressure21,23,24, our finding that schizophrenia risk variants that persist at common allele frequencies are enriched in LoF-intolerant genes might appear counterintuitive. However, new evidence presented here suggests that this can be reconciled by BGS, which is a consequence of purifying selection in regions of low recombination45,46. In such regions, recurrent selection against deleterious variants causes haplotypes to be removed from the gene pool, which reduces genetic diversity in a manner equivalent to a reduction in effective population size47. This in turn impairs the efficiency of the selection process, allowing alleles with small deleterious effects to rise in frequency by drift48. Such a consequence of purifying selection has been shown to be compatible with the genomic architecture of complex human traits49 and to influence phenotypes in model organisms50. We have explicitly modeled this effect (both theoretically and via simulations; Supplementary Note) and provide strong evidence for the feasibility of this effect as explanatory for the effect sizes seen for common alleles in schizophrenia.
