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Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

Author

Listed:
  • Andrew P. Morris

    (University of Liverpool
    University of Oxford)

  • Thu H. Le

    (University of Virginia)

  • Haojia Wu

    (Washington University School of Medicine)

  • Artur Akbarov

    (University of Manchester)

  • Peter J. van der Most

    (University of Groningen, University Medical Center Groningen)

  • Gibran Hemani

    (University of Bristol)

  • George Davey Smith

    (University of Bristol)

  • Anubha Mahajan

    (University of Oxford)

  • Kyle J. Gaulton

    (University of California, San Diego)

  • Girish N. Nadkarni

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Adan Valladares-Salgado

    (Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social)

  • Niels Wacher-Rodarte

    (Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social)

  • Josyf C. Mychaleckyj

    (University of Virginia School of Medicine)

  • Nicole D. Dueker

    (University of Miami Miller School of Medicine)

  • Xiuqing Guo

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Yang Hai

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Jeffrey Haessler

    (Fred Hutchinson Cancer Research Center)

  • Yoichiro Kamatani

    (Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences)

  • Adrienne M. Stilp

    (University of Washington)

  • Gu Zhu

    (QIMR Berghofer Medical Research Institute)

  • James P. Cook

    (University of Liverpool)

  • Johan Ärnlöv

    (Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet
    School of Health and Social Studies, Dalarna University)

  • Susan H. Blanton

    (University of Miami Miller School of Medicine
    University of Miami)

  • Martin H. de Borst

    (Division of Nephrology, University of Groningen, University Medical Center Groningen)

  • Erwin P. Bottinger

    (Icahn School of Medicine at Mount Sinai)

  • Thomas A. Buchanan

    (Keck School of Medicine of USC)

  • Sylvia Cechova

    (University of Virginia)

  • Fadi J. Charchar

    (Federation University Australia
    University of Leicester
    University of Melbourne)

  • Pei-Lun Chu

    (Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University)

  • Jeffrey Damman

    (Erasmus Medical Center Rotterdam)

  • James Eales

    (University of Manchester)

  • Ali G. Gharavi

    (Division of Nephrology, College of Physicians and Surgeons, Columbia University)

  • Vilmantas Giedraitis

    (Molecular Geriatrics, Uppsala University)

  • Andrew C. Heath

    (Washington University in St Louis)

  • Eli Ipp

    (University of California Los Angeles
    Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center)

  • Krzysztof Kiryluk

    (Division of Nephrology, College of Physicians and Surgeons, Columbia University)

  • Holly J. Kramer

    (Loyola University Medical Center)

  • Michiaki Kubo

    (RIKEN Center for Integrative Medical Sciences)

  • Anders Larsson

    (Clinical Epidemiology, Uppsala University)

  • Cecilia M. Lindgren

    (University of Oxford
    University of Oxford
    Broad Institute of Harvard and MIT)

  • Yingchang Lu

    (Icahn School of Medicine at Mount Sinai)

  • Pamela A. F. Madden

    (Washington University in St Louis)

  • Grant W. Montgomery

    (University of Queensland)

  • George J. Papanicolaou

    (National Heart, Lung and Blood Institute)

  • Leslie J. Raffel

    (University of California)

  • Ralph L. Sacco

    (Miller School of Medicine, University of Miami
    University of Miami
    University of Miami)

  • Elena Sanchez

    (Division of Nephrology, College of Physicians and Surgeons, Columbia University)

  • Holger Stark

    (Heinrich Heine University Düsseldorf)

  • Johan Sundstrom

    (Clinical Epidemiology, Uppsala University)

  • Kent D. Taylor

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Anny H. Xiang

    (Kaiser Permanente Southern California)

  • Aleksandra Zivkovic

    (Heinrich Heine University Düsseldorf)

  • Lars Lind

    (Clinical Epidemiology, Uppsala University)

  • Erik Ingelsson

    (Stanford University School of Medicine
    Stanford University
    Stanford Diabetes Research Center, Stanford University
    Molecular Epidemiology and Science for Life Laboratory, Uppsala University)

  • Nicholas G. Martin

    (QIMR Berghofer Medical Research Institute)

  • John B. Whitfield

    (QIMR Berghofer Medical Research Institute)

  • Jianwen Cai

    (University of North Carolina at Chapel Hill)

  • Cathy C. Laurie

    (University of Washington)

  • Yukinori Okada

    (Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences
    Osaka University Graduate School of Medicine)

  • Koichi Matsuda

    (University of Tokyo)

  • Charles Kooperberg

    (Fred Hutchinson Cancer Research Center)

  • Yii-Der Ida Chen

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Tatjana Rundek

    (Miller School of Medicine, University of Miami
    University of Miami)

  • Stephen S. Rich

    (University of Virginia School of Medicine)

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Esteban J. Parra

    (University of Toronto at Mississauga)

  • Miguel Cruz

    (Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social)

  • Jerome I. Rotter

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Harold Snieder

    (University of Groningen, University Medical Center Groningen)

  • Maciej Tomaszewski

    (University of Manchester
    Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre)

  • Benjamin D. Humphreys

    (Washington University School of Medicine)

  • Nora Franceschini

    (University of North Carolina)

Abstract

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Suggested Citation

  • Andrew P. Morris & Thu H. Le & Haojia Wu & Artur Akbarov & Peter J. van der Most & Gibran Hemani & George Davey Smith & Anubha Mahajan & Kyle J. Gaulton & Girish N. Nadkarni & Adan Valladares-Salgado , 2019. "Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07867-7
    DOI: 10.1038/s41467-018-07867-7
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    Cited by:

    1. Matthias Wuttke & Eva König & Maria-Alexandra Katsara & Holger Kirsten & Saeed Khomeijani Farahani & Alexander Teumer & Yong Li & Martin Lang & Burulca Göcmen & Cristian Pattaro & Dorothee Günzel & An, 2023. "Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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