Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns

Abstract

Identifying Mendelian diseases with recessive inheritance is challenging as the majority of cases are caused by compound heterozygous genotypes which require sequencing data in families to definitively identify. Bottleneck events, such as in the Finnish population, enrich specific homozygous variants to higher frequencies and thus facilitate identification of disease associations through easily recognized homozygous genotypes. Here, we study homozygous and heterozygous effects of 82,516 coding variants on 2,444 disease endpoints using nationwide electronic health record (EHR) data of 176,899 Finns. We find known and novel associations to homozygous genotypes across a broad spectrum of phenotypes such as retinal dystrophy, adult-onset cataract and female infertility (13/20 of which would have been missed by the traditional additive GWAS model). With these results, and supporting simulations, we demonstrate the added benefit of homozygous scans in GWAS. We further use these results to explore inheritance patterns of known Mendelian variants. We find many Mendelian variants whose inheritance cannot be adequately described with the traditional definition of dominant or recessive. In particular, we find disease risk in heterozygous carriers of variants known to cause disease with recessive inheritance, as well as for variants labeled benign in ClinVar. Our results demonstrate how biobank efforts, particularly in founder populations, can broaden our understanding of the impact of genetic variants.

Influence of autozygosity on common disease risk across the phenotypic spectrum

“…Via simulations, we show that the associations we detected are unlikely to be due to autozygosity increasing additive variance for genetic risk of binary traits, suggesting wide-spread non-additive effects. In the few studies that have looked, recessive-acting rare and common variants have been found to be associated with multiple common diseases including T2D [45][46][47] . However, it has been previously shown that dominance heritability at common variants is negligible 48,49 , suggesting the observed F ROH associations likely stem from non-additive effects at low allele frequency variants and/or epistasis.…”

FinnGen: Unique genetic insights from combining isolated population and national health register data

“…These associations demonstrate that imputation using a population specific genotyping array and imputation panel combined with national registry-based phenotyping in the isolated Finnish population can successfully identify associations and fine-map causal variants even in rare variants and phenotypes. An extended study of ClinVar variants as well as variants with novel bi-allelic Mendelian effects in FinnGen is described in an accompanying paper by Heyne et al 22 .…”

The Finnish genetic heritage in 2022 – from diagnosis to translational research

“…There are also examples where the allele frequency of a certain variant is much smaller in Finns than in an admixed European sample, and vice versa, while there are variants enriched in Finns that occur at much lower frequencies in the European population. The preprint by Heyne et al (2021) suggests that Finnish genomes harbor fewer detectable variants for recessively inherited disease variants than non-Finnish Europeans, but those that are detected have larger MAFs. Therefore, alongside the FDH, Finnish genomes are also enriched for variants linked to more genetically complex diseases, which can facilitate discoveries in the common complex disease spectrum with implications beyond this single population.…”