Reproductive and cognitive effects in carriers of recessive pathogenic variants

The genetic landscape of human Mendelian diseases is shaped by mutation and selection. Selection is mediated by phenotypic effects which interfere with health and reproductive success. Although selection on heterozygotes is well-established in autosomal dominant disorders, convincing evidence for selection in carriers of pathogenic variants associated with recessive conditions is limited, with only a few specific cases documented. We studied heterozygous pathogenic variants in 1,929 genes, which cause recessive diseases when bi-allelic, in a cohort of 378,751 unrelated European individuals from the UK Biobank1. We assessed the impact of these pathogenic variants on reproductive success. We find evidence for fitness effects in heterozygous carriers for recessive genes, especially for variants in constrained genes across a broad range of diseases. Our data suggest reproductive effects at the population level, and hence natural selection, for autosomal recessive disease variants. We further show that variants in genes that underlie intellectual disability are associated with reduced cognition measures in carriers. In concordance with this, we observe an altered genetic landscape, characterized by a threefold reduction in the calculated frequency of biallelic intellectual disability in the population relative to other recessive disorders. The existence of phenotypic and selective effects of pathogenic variants in constrained recessive genes is consistent with a gradient of heterozygote effects, rather than a strict dominant-recessive dichotomy2.