It has been suggested that clustering of risk alleles in mutationintolerant genes is a hallmark of early-onset traits under natural selection23,24. However, LoF-intolerant genes are known to be enriched for SNPs identified as genome-wide significant in GWAS (as listed in the NHGRI-EBI GWAS Catalog25) and for broad categories of disorders21. To examine whether our finding is a property of polygenic disorders in general, we obtained summary genetic data from a late-onset neuropsychiatric disorder (Alzheimer’s disease), a non-psychiatric disorder (type 2 diabetes) and a psychological trait (neuroticism), each of which has been shown to be under minimal selective pressure (Methods). These other phenotypes showed at best a weak signal for enrichment of the LoF-intolerant gene set in the MAGMA analysis, with the signal not comparable to that seen in schizophrenia (Alzheimer’s disease, P = 0.008; type 2 diabetes, P = 0.016; neuroticism, P = 0.066).
