Diverse ancestry whole-genome sequencing association study identifies <i>TBX5</i> and <i>PTK7</i> as susceptibility genes for posterior urethral valves.

Abstract

Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this rare disorder remains unknown. We performed a sequencing-based genome-wide association study (seqGWAS) in 132 unrelated male PUV cases and 23,727 controls of diverse ancestry, identifying statistically significant associations with common variants at 12q24.21 (p=7.8 × 10^-12; OR 0.4) and rare variants at 6p21.1 (p=2.0 × 10^-8; OR 7.2), that were replicated in an independent European cohort of 395 cases and 4151 controls. Fine mapping and functional genomic data mapped these loci to the transcription factor <i>TBX5</i> and planar cell polarity gene <i>PTK7</i>, respectively, the encoded proteins of which were detected in the developing urinary tract of human embryos. We also observed enrichment of rare structural variation intersecting with candidate <i>cis</i>-regulatory elements, particularly inversions predicted to affect chromatin looping (p=3.1 × 10^-5). These findings represent the first robust genetic associations of PUV, providing novel insights into the underlying biology of this poorly understood disorder and demonstrate how a diverse ancestry seqGWAS can be used for disease locus discovery in a rare disease.