Mono- and Biallelic Variant Effects on Disease at Biobank Scale

Abstract

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics 1 . Population bottleneck events, such as in the Finnish population history, enrich some homozygous variants to higher frequencies which facilitates the identification of variants that cause disease with recessive inheritance 2,3 . Here, we study homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using nationwide electronic health record (EHR) data of 176,899 Finns. We find associations for homozygous genotypes across a broad spectrum of phenotypes including known associations to retinal dystrophy, and novel associations to adult-onset cataract and female infertility. 13/20 of recessive disease associations would have been missed by the additive model traditionally used in genome-wide association studies (GWAS). We further use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a traditional definition of dominant or recessive. In particular, we find significant heterozygous effects of variants known to cause disease with recessive inheritance, as well as for reported benign variants. Our results demonstrate how biobanks, particularly in founder populations, can broaden our understanding of the sometimes more complex dosage effects of Mendelian variants on disease.