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

Content Provider	Europe PMC
Author	Chan, Melanie MY Sadeghi-Alavijeh, Omid Lopes, Filipa M Hilger, Alina C Stanescu, Horia C Voinescu, Catalin D Beaman, Glenda M Newman, William G Zaniew, Marcin Weber, Stefanie Ho, Yee Mang Connolly, John O Wood, Dan Maj, Carlo Stuckey, Alexander Kousathanas, Athanasios Kleta, Robert Woolf, Adrian S Bockenhauer, Detlef Levine, Adam P Gale, Daniel P
Editor	Germino, Gregory G Pollak, Martin R
Copyright Year	2022
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 TBX5 and planar cell polarity gene PTK7, 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 cis-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.
Journal	eLife
Volume Number	11
PubMed Central reference number	PMC9512401
PubMed reference number	36124557
e-ISSN	2050084X
DOI	10.7554/elife.74777
Language	English
Publisher	eLife Sciences Publications, Ltd
Publisher Date	2022-09-20
Access Restriction	Open
Rights License	This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. © 2022, Chan et al
Subject Keyword	whole-genome sequencing genome-wide association study seqGWAS CAKUT PUV posterior urethral valves Human
Content Type	Text
Resource Type	Article
Subject	Immunology and Microbiology Neuroscience Medicine Biochemistry, Genetics and Molecular Biology