#1761 Whole-genome sequencing reveals contribution of rare and common variation to structural kidney and urinary tract malformations

Abstract

Abstract Background and Aims Structural kidney and urinary tract malformations are the commonest cause of kidney failure in children and young adults. Targeted and whole-exome sequencing has identified over 50 monogenic causes for these phenotypically heterogeneous conditions but have largely focused on cohorts enriched for familial, syndromic, or consanguineous disease. We sought to better characterise the genetic architecture of these conditions using whole genome sequencing (WGS) data from the UK's 100 000 Genomes Project. Method 992 unrelated individuals with structural kidney and urinary tract malformations were assessed using the Genomics England clinical interpretation pipeline to determine a genetic diagnosis. Statistically robust case-control association testing was performed using WGS data from a subset of 813 patients and 25 205 ancestry-matched unaffected individuals seeking enrichment of common and rare single-nucleotide and structural variants (SNV/SVs) on a genome-wide, per-gene, and cis-regulatory element basis. Heritability analysis was carried out in 623 cases and 20 060 controls of European ancestry with polygenic risk scores (PRS) derived for each of the six phenotypes. The PUV-PRS was validated in an independent cohort of 77 patients from the AGORA data- and biobank and an additional 2 746 European controls. Results The overall diagnostic yield was 4.3% (43/992; Fig. 1) with age < 18 years (P = 2.0 × 10−4), family history (P = 7.5 × 10−3) and extra-renal features (P = 1.9 × 10−4) all independent predictors of a genetic diagnosis. The diagnostic yield was higher in cases with cystic kidney dysplasia (10.7%) or kidney anomalies (5.9%). HNF1B was the most frequently identified cause. Exome-wide rare variant analysis identified enrichment of SNV/indels affecting AUTS2 (P = 3.7 × 10−6), ARHGAP5 (P=6.0 × 10−6), known kidney malformation gene HNF1B (P = 6.1 × 10−6), and ZNF879 (P=7.0 × 10−6), all of which have been previously implicated in developmental and/or cancer pathways. An increased burden of rare SVs affecting HNF1B (P = 3.1 × 10−4) was observed. There was no evidence of enrichment for cis-regulatory element disrupting SVs. Genome-wide testing of 19 million common and low-frequency variants (minor allele frequency > 0.1%) did not detect any individual variants that were significantly associated in the total cohort, but together these variants were estimated to contribute to 23% (standard error 11%) of the heritability of kidney and urinary tract malformations in cases with European ancestry. Comparison of phenotype-specific PRS showed considerable overlap between kidney anomalies, cystic kidney dysplasia, obstructive uropathy and vesico-ureteric reflux but the polygenic contribution to PUV and bladder exstrophy was distinct (Fig. 2). A PUV-PRS consisting of 36, 106 variants was validated in an independent European cohort of 77 cases and 2 746 controls (empirical P = 1 × 10−4). Conclusion We show that non-Mendelian genomic factors are important for the pathogenesis of structural kidney and urinary tract malformations, supported by the observation that a minority of patients in this large unselected cohort have a monogenic diagnosis. In addition, a significant proportion of heritability can be attributed to common and low-frequency variation and there is overlap in the polygenic contributors to upper urinary tract malformations with distinct polygenic signatures relevant to PUV and bladder exstrophy. Larger cohorts of patients are needed to increase power to detect variants contributing to this heritability and identify biological mechanisms and pathways important for kidney and urinary tract development.