Whole-genome sequencing reveals contribution of rare and common variation to structural kidney and urinary tract malformations

IntroductionCongenital anomalies of the kidneys and urinary tract (CAKUT) are the commonest cause of kidney failure in children and young adults. Over 50 monogenic causes have been identified, however less than 20% of patients have a genetic diagnosis identified using targeted or whole exome sequencing. We sought to characterise the genomic architecture of CAKUT using whole genome sequencing (WGS). MethodsUsing WGS from 1,052 unrelated individuals with CAKUT recruited to the UKs 100,000 Genomes Project, we determined diagnostic yield and looked for gene-based enrichment of rare variants exome-wide. We performed sequencing based genome-wide association studies (seqGWAS) and used these results to estimate the heritability explained by common variants. ResultsThe overall diagnostic yield was 4.9% with family history (P=0.02; OR 2.2; 95% CI 1.1-4.4), consanguinity (P=0.01; OR 3.0; 95%CI 1.2-6.9) and extra-renal features (P=1.1x10-4; OR 3.1; 95% CI 1.7-5.7) independently predicting a monogenic diagnosis. Diagnostic yield was highest in cystic kidney dysplasia (11.1%) and kidney agenesis/hypodysplasia (7.4%). Exome-wide rare variant and genome-wide common variant (minor allele frequency [MAF] [&ge;] 0.5%) association testing in a subset of 813 patients and 25,205 ancestry-matched controls identified significant association at 6q16.3 (rs117473527; P=4.83x10-8; OR 3.13; 95% CI 2.08-4.72; MAF 0.01) which requires replication. Common variants were estimated to explain up to 23% of the phenotypic variance observed in CAKUT in those with European ancestry suggesting that larger studies are needed to recover some of this missing heritability. A genomic risk score for posterior urethral valves was also validated in an independent European cohort of 77 cases and 2,746 controls (P<0.001). ConclusionsOnly a minority of patients in this large, unselected cohort received a monogenic diagnosis, with common variants estimated to account for a substantial proportion of phenotypic heritability. This suggests that non-Mendelian genomic factors may be important for the pathogenesis of CAKUT. Lay SummaryThis study shows that single-gene causes of isolated and non-familial CAKUT are rare, and that genomic testing should be targeted towards those with kidney cysts and/or small kidneys that have not formed properly in the womb. Individuals with a close relative with CAKUT and those with involvement of other organ systems were more likely to receive a genetic diagnosis. These data support a possible polygenic basis for CAKUT, where many common DNA changes cumulatively affect risk, particularly in posterior urethral valves, the most common cause of kidney failure in boys. Larger collaborative genomic studies are needed to increase our ability to identify these DNA changes and the mechanisms and pathways important for kidney and urinary tract development.