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

  1. Melanie Mai Yee Chan
  2. Omid Sadeghi-Alavijeh
  3. Filipa M Lopes
  4. Alina C Hilger
  5. Horia C Stanescu
  6. Catalin D Voinescu
  7. Glenda M Beaman
  8. William G Newman
  9. Marcin Zaniew
  10. Stefanie Weber
  11. Yee Mang Ho
  12. John O Connolly
  13. Dan Wood
  14. Carlo Maj
  15. Alexander Stuckey
  16. Athanasios Kousathanas
  17. Genomics England Research Consortium
  18. Robert Kleta
  19. Adrian S Woolf
  20. Detlef Bockenhauer
  21. Adam P Levine
  22. Daniel P Gale  Is a corresponding author
  1. University College London, United Kingdom
  2. University of Manchester, United Kingdom
  3. University of Bonn, Germany
  4. University of Zielona Góra, Poland
  5. University of Marburg, Germany
  6. University College London Hospitals NHS Foundation Trust, United Kingdom
  7. 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 following previously published data sets were used

Article and author information

Author details

  1. Melanie Mai Yee Chan

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1968-1734
  2. Omid Sadeghi-Alavijeh

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Filipa M Lopes

    School of Biological Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Alina C Hilger

    Children's Hospital, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Horia C Stanescu

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Catalin D Voinescu

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3636-8689
  7. Glenda M Beaman

    Manchester Centre for Genomic Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. William G Newman

    Manchester Centre for Genomic Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Marcin Zaniew

    Department of Pediatrics, University of Zielona Góra, Zielona Gora, Poland
    Competing interests
    The authors declare that no competing interests exist.
  10. Stefanie Weber

    Department of Pediatric Nephrology, University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Yee Mang Ho

    School of Biological Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. John O Connolly

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Dan Wood

    Department of Adolescent Urology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Carlo Maj

    Center for Human Genetics, University of Marburg, Marburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Alexander Stuckey

    Genomics England, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Athanasios Kousathanas

    Genomics England, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Genomics England Research Consortium

  18. Robert Kleta

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Adrian S Woolf

    School of Biological Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5541-1358
  20. Detlef Bockenhauer

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Adam P Levine

    Department of Renal Medicine, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  22. Daniel P Gale

    Department of Renal Medicine, University College London, London, United Kingdom
    For correspondence
    d.gale@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9170-1579

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/).

Reviewing Editor

  1. Gregory G Germino, National Institutes of Health, United States

Version history

  1. Preprint posted: August 10, 2021 (view preprint)
  2. Received: October 17, 2021
  3. Accepted: August 15, 2022
  4. Accepted Manuscript published: September 20, 2022 (version 1)
  5. Version of Record published: September 26, 2022 (version 2)

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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  1. Melanie Mai Yee Chan
  2. Omid Sadeghi-Alavijeh
  3. Filipa M Lopes
  4. Alina C Hilger
  5. Horia C Stanescu
  6. Catalin D Voinescu
  7. Glenda M Beaman
  8. William G Newman
  9. Marcin Zaniew
  10. Stefanie Weber
  11. Yee Mang Ho
  12. John O Connolly
  13. Dan Wood
  14. Carlo Maj
  15. Alexander Stuckey
  16. Athanasios Kousathanas
  17. Genomics England Research Consortium
  18. Robert Kleta
  19. Adrian S Woolf
  20. Detlef Bockenhauer
  21. Adam P Levine
  22. Daniel P Gale
(2022)
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

Share this article

https://doi.org/10.7554/eLife.74777

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