Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves
- University College London, United Kingdom
- University of Manchester, United Kingdom
- University of Bonn, Germany
- University of Zielona Góra, Poland
- University of Marburg, Germany
- University College London Hospitals NHS Foundation Trust, United Kingdom
- Queen Mary University of London, United Kingdom
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=7.8x10-12; OR 0.4) and rare variants at 6p21.1 (P=2.0x10-8; OR 7.2), that were replicated in an independent European cohort of 395 cases and 4,151 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=3.1x10-5). 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.
Data availability
All genetic and phenotypic data from the 100,000 Genomes Project and can be accessed by application to Genomics England Ltd (https://www.genomicsengland.co.uk/about-gecip/joining-research-community/). Access is free for academic research institutions and universities as well as public and private healthcare organsisations that undertake significant research activity. This dataset includes de-identified, linked information for each participant including genome sequence data, variant call files, phenotype/clinical data and Hospital Episode Statistics (HES) with access gained through a secure Research Environment. No sequencing or identifiable personal data is available for download.The full GWAS summary statistics have been uploaded to the NHGRI-EBI GWAS Catalog prior to publication.Source Data files have been provided for Figures 2, 6, 9 and 10 containing the numerical data used to generate figures.Custom R Code for the case-control ancestry-matching algorithm can be found at https://github.com/APLevine/PCA_Matching.Code for SAIGE and SAIGE-GENE can be found at https://github.com/weizhouUMICH/SAIGE.Code for PAINTOR is available at https://github.com/gkichaev/PAINTOR_V3.0.Functional annotation and MAGMA gene and gene-set analysis were performed using the web-based platform FUMA (https://fuma.ctglab.nl).Custom R code for the structural variant burden analysis has been uploaded as SV Burden Testing - Source Code 1.
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Article and author information
Author details
Melanie Mai Yee Chan
Catalin D Voinescu
Funding
Kidney Research UK (TF_004_20161125)
- Melanie Mai Yee Chan
Medical Research Council (MR/S021329/1)
- Omid Sadeghi-Alavijeh
Medical Research Council (MR/T016809/1)
- Adrian S Woolf
St Peter's Trust for Kidney Bladder and Prostate Research
- Daniel P Gale
National Institute for Health and Care Research
- Adam P Levine
Kidney Research UK (Paed_RP_002_20190925)
- Glenda M Beaman
- William G Newman
- Adrian S Woolf
BONFOR-Gerok Grant
- Alina C Hilger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Ethical approval for the 100,000 Genomes Project was granted by the Research Ethics Committee for East of England - Cambridge South (REC Ref 14/EE/1112). Written informed consent was obtained from all participants and/or their guardians.Human embryonic tissues, collected after maternal consent and ethical approval (REC18/NE/0290), were sourced from the Medical Research Council and Wellcome Trust Human Developmental Biology Resource (https://www.hdbr.org/).
Copyright
© 2022, Chan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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