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.
-
The GTEx Consortium atlas of genetic regulatory effects across human tissuesGTEx (V8), doi: 10.1126/science.aaz1776.
-
Expanded encyclopaedias of DNA elements in the human and mouse genomesENCODE, doi:10.1038/s41586-020-2493-4.
-
Integrative analysis of 111 reference human epigenomesRoadmap Epigneomics Project, doi: 10.1038/nature14248.
-
Chromatin architecture reorganization during stem cell differentiationNCBI Gene Expression Omnibus, GSE52457, doi: 10.1038/nature14222.
-
JASPAR 2020: update of the open-access database of transcription factor binding profilesJASPAR (2020), doi: 10.1093/nar/gkz1001.
-
The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.GCST002890, DOI: 10.1093/nar/gky1120.
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.
Metrics
-
- 1,145
- views
-
- 223
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves
eLife 11:e74777.
https://doi.org/10.7554/eLife.74777
Further reading
-
- Cell Biology
- Developmental Biology
The formation of large endolysosomal structures in unfertilized eggs ensures that lysosomes remain dormant before fertilization, and then shift into clean-up mode after the egg-to-embryo transition.
-
- Developmental Biology
Ribonucleoprotein (RNP) granules are membraneless electron-dense structures rich in RNAs and proteins, and involved in various cellular processes. Two RNP granules in male germ cells, intermitochondrial cement and the chromatoid body (CB), are associated with PIWI-interacting RNAs (piRNAs) and are required for transposon silencing and spermatogenesis. Other RNP granules in male germ cells, the reticulated body and CB remnants, are also essential for spermiogenesis. In this study, we disrupted FBXO24, a testis-enriched F-box protein, in mice and found numerous membraneless electron-dense granules accumulated in sperm flagella. Fbxo24 knockout (KO) mice exhibited malformed flagellar structures, impaired sperm motility, and male infertility, likely due to the accumulation of abnormal granules. The amount and localization of known RNP granule-related proteins were not disrupted in Fbxo24 KO mice, suggesting that the accumulated granules were distinct from known RNP granules. Further studies revealed that RNAs and two importins, IPO5 and KPNB1, abnormally accumulated in Fbxo24 KO spermatozoa and that FBXO24 could ubiquitinate IPO5. In addition, IPO5 and KPNB1 were recruited to stress granules, RNP complexes, when cells were treated with oxidative stress or a proteasome inhibitor. These results suggest that FBXO24 is involved in the degradation of IPO5, disruption of which may lead to the accumulation of abnormal RNP granules in sperm flagella.
