This leads to higher rates of homozygosity, and increases the chance occurrence of pathogenic variants in a homozygous state that lead to diseases with recessive inheritance. As a result, the Finnish population is characterized by higher rates of DNA stretches with a common origin 6, 7 carrying particular sets of genetic variants. The Finnish population has experienced such bottleneck events and has been, historically, relatively isolated from other European populations 5.

By contrast, in populations that have encountered a recent reduction in population size, certain founder diseases with recessive inheritance are present at higher frequencies. Identifying variants that influence disease risk only in the homozygous state (recessive inheritance) is particularly challenging, as the square of variant frequencies means that the homozygous state is often exceedingly rare. Rare genetic variants with large effects on disease can have direct implications for the development of potential treatments 1 however, studying their effects comprehensively requires large, broadly phenotyped samples 4. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease. Similarly, we find presumed benign variants with disease effects. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies.

We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Here we examine the 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. 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 2, 3. Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics 1.

Mono disease