Mixed ancestry analysis of whole-genome sequencing reveals common, rare, and structural variants associated with posterior urethral valves

Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this disorder remains largely unknown. To address this, we analyzed whole-genome sequencing (WGS) data from 132 unrelated PUV cases and 23,727 controls of mixed ancestry. We observed enrichment of rare structural variation intersecting with candidate cis-regulatory elements, particularly inversions predicted to affect chromatin looping (P=3.1x10-5). We also identified statistically significant associations with common variants at 12q24.21 (P=7.8x10-12; OR 0.4) and uncommon variants at 6p21.1 (P=2x10-8; OR 7.2), that were replicated in an independent European cohort. Bayesian fine mapping and functional annotation mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7, respectively, providing insights into the biological pathways underlying PUV. These findings demonstrate that a well-controlled diverse ancestry WGS approach can reveal the genetic architecture of a complex disorder by increasing power for disease locus discovery and facilitating fine-mapping of causal variants.