Congenital anomalies of the kidneys and urinary tract (CAKUT) are the commonest cause of kidney failure in children and young adults with over 50 monogenic causes identified, largely in cohorts enriched for familial, syndromic, or consanguineous disease. We sought to better characterise the genomic architecture of these conditions using whole genome sequencing data from 992 unrelated individuals recruited to the UKs 100,000 Genomes Project. The overall diagnostic yield was 4.3% with family history (P=7.4x10-3; OR 2.7; 95% CI 1.3-5.4) and extra-renal features (P=2.0x10-4; OR 3.4; 95% CI 1.8-6.6) independently predicting a monogenic diagnosis. Diagnostic yield was highest in cystic kidney dysplasia (10.7%) and kidney agenesis/hypodysplasia (5.9%). Exome-wide rare variant and genome-wide common variant (minor allele frequency ≤ 0.1%) testing was performed in a subset of 813 patients and 25,205 ancestry-matched controls with significant association detected at rs117473527 (P=3.93x10-8; OR 3.17; 95% CI 2.10-4.78; MAF 0.02). Heritability analysis estimated common variants explain 23% (standard error 11%) of phenotypic variance in those with European ancestry. Comparison of phenotype-specific genomic risk scores (GRS) demonstrated shared polygenic aetiology between upper urinary tract phenotypes but distinct patterns for both posterior urethral valves (PUV) and bladder exstrophy. A PUV-GRS consisting of 36,106 variants was validated in an independent European cohort of 77 cases and 2,746 controls (P=1x10-4) accounting for 37% of phenotypic variance. Together, these data demonstrate the importance of non-Mendelian genomic factors in the pathogenesis of CAKUT, evidenced by the fact that only a minority of patients in this large, unselected cohort received a monogenic diagnosis and that a substantial proportion of heritability can be attributed to common variation.

MFS discloses consultant fees from Bayer, Santhera, and Travere Therapeutics.

MMYC was supported by a Kidney Research UK Clinical Research Fellowship (TF_004_20161125) and the Medical Research Council (MR/Y008170/1). OSA is funded by an MRC Clinical Research Training Fellowship (MR/S021329/1). SGW was supported by a Young Investigator Grant from the ESPN. LvdZ SGW and LV were supported by a consortium grant from the Dutch Kidney Foundation (20OC002). APL is supported by an NIHR Academic Clinical Lectureship. DPG is supported by the St Peters Trust for Kidney Bladder and Prostate Research.  

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All data was available through Genomics England prior to this study. Genomic and phenotype data from participants recruited to the 100,000 Genomes Project can be accessed by application to Genomics England Ltd at https://www.genomicsengland.co.uk/about-gecip/joining-research-community/.

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Supplementary Tables can be found at https://doi.org/10.5281/zenodo.13834253. Genomic and phenotype data from participants recruited to the 100,000 Genomes Project can be accessed by application to Genomics England Ltd at https://www.genomicsengland.co.uk/about-gecip/joining-research-community/. Details of the WGS aggregated dataset used for the analysis can be found at https://re-docs.genomicsengland.co.uk/aggv2/. Code for the case control ancestry matching algorithm can be found at https://github.com/APLevine/PCA_Matching. Details of the rare variant workflow can be found at https://re-docs.genomicsengland.co.uk/avt/. Details of the common variant GWAS workflow can be found at https://re-docs.genomicsengland.co.uk/gwas/. GWAS summary statistics will be made publicly available via the GWAS catalog on publication (https://www.ebi.ac.uk/gwas/).

https://doi.org/10.5281/zenodo.13834253

https://github.com/APLevine/PCA_Matching

https://www.genomicsengland.co.uk/about-gecip/joining-research-community/