Mono- and biallelic variant effects on disease at biobank scale
Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance. In this work published in Nature by CGM Investigators Mark Daly, Aarno Palotie, Heidi Rehm, and colleagues, the richness of FinnGen was leveraged to examine homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. They found associations for homozygous genotypes across a broad spectrum of phenotypes, including recessive disease associations that would have been missed by the additive model that is typically used in genome-wide association studies. Importantly, the group also found variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects, and presumed benign variants with disease effects. This work powerfully illuminates how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.