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.

The authors have declared no competing interest.

OSA is funded by an MRC Clinical Research Training Fellowship (MR/S021329/1). MYC is funded by a Kidney Research UK Clinical Research Fellowship (TF_004_20161125). DPG is supported by the St Peters Trust for Kidney, Bladder and Prostate Research.

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Ethical approval for the 100,000 genome project was granted by the Research Ethics Committee for East of England Cambridge South (REC Ref: 14/EE/1112).

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