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 genetics1. 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 inheritance2,3. 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. 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. 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 use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

FinnGen provides genetic insights from a well-phenotyped isolated population

“…Furthermore, a known pathogenic recessively acting missense variant in CERKL was associated with hereditary retinal dystrophy (p.Cys125Trp; AF FinnGen = 0.6%, gnomAD NFSEE = 0%; OR = 98,716, P = 5.15 × 10 −25 ). This association is, however, driven by compound heterozygotes, as previously detailed 13 . These associations demonstrate that imputation using a population-specific genotyping array and an 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.…”

“…These associations demonstrate that imputation using a population-specific genotyping array and an 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 and variants with specific biallelic Mendelian effects in FinnGen is provided in a companion paper 13 .…”

Precise modulation of transcription factor levels identifies features underlying dosage sensitivity

“…Our model allows for both robustness and phenotypic sensitivity to TF dosage. Robustness can be explained by nonlinear relationships between gene dosage and phenotype suggested by human 56 , 57 and mouse 58 genetics. Our model suggests that these relationships may be a composite of distinct molecular responses: most SOX9 targets are buffered against moderate changes in SOX9 dosage, while trait variation and disease is primarily driven by the SOX9-sensitive effectors.…”

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum

“…Our large-scale genetic investigation of infertility and related reproductive phenotypes in over 1 million individuals identified 19 genetic loci associated with female infertility, two with male infertility, and novel variants for the reproductive hormones FSH (3 novel variants), LH (1), oestradiol (1), and total testosterone (28) in women and for total testosterone in men (39). Through rare-variant and gene-based analyses in the UK Biobank, we additionally identified PLEKHG4 associated with female infertility and 50 genes for testosterone, including the first reported hormone-associated variants in some members of the hydroxysteroid dehydrogenase enzyme family.…”