Contribution of variants across the allelic frequency spectrum to cystic kidney disease

Cystic kidney disease (CyKD) is a predominantly familial disease. Gene discovery has been led by family-based and candidate gene studies, limiting the ascertainment of additional genome-wide variants involved. Taking whole genome sequencing data from the 100,000 Genomes Project, we used hypothesis-free approaches to systematically characterize and quantify genetic contributors to CyKD across variant types and the allelic spectrum in 1,209 cases and 26,096 ancestry-matched controls. In 82.3% CyKD cases a likely disease-causing monogenic variant was identified. There was an enrichment of rare coding, splicing and structural variants in known CyKD genes, and novel gene-based signals in COL4A3 and (monoallelic) PKHD1. The risks of these variants to CyKD were quantified, with lower risk seen in more recently described genes. Meta-analysis of common variants across four international biobanks did not reveal any associations. Common variants accounted for 3-9% of the heritability of CyKD across three European ancestry cohorts. This represents an unbiased examination of the genetic architecture of a national CyKD cohort using robust statistical methodology. We have quantified the contribution of coding, non-coding, and structural variants to CyKD, and the small contribution of common variants to its heritability. These findings will inform genetic testing and counselling strategies in the clinic.