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

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, Niels Wacher-Rodarte, Josyf C. Mychaleckyj, Nicole D. Dueker, Xiuqing Guo, Yang Hai, Jeffrey Haessler, Yoichiro Kamatani, Adrienne M. Stilp, Gu Zhu, James P. Cook, Johan Ärnlöv, Susan H. Blanton, Martin H. de Borst, Erwin P. Bottinger, Thomas A. Buchanan, Sylvia Cechova, Fadi J. Charchar, Pei-Lun Chu, Jeffrey Damman, James Eales, Ali G. Gharavi, Vilmantas Giedraitis, Andrew C. Heath, Eli Ipp, Krzysztof Kiryluk, Holly J. Kramer, Michiaki Kubo, Anders Larsson, Cecilia M. Lindgren, Yingchang Lu, Pamela A. F. Madden, Grant W. Montgomery, George J. Papanicolaou, Leslie J. Raffel, Ralph L. Sacco, Elena Sanchez, Holger Stark, Johan Sundstrom, Kent D. Taylor, Anny H. Xiang, Aleksandra Zivkovic, Lars Lind, Erik Ingelsson, Nicholas G. Martin, John B. Whitfield, Jianwen Cai, Cathy C. Laurie, Yukinori Okada, Koichi Matsuda, Charles Kooperberg, Yii- Der Ida Chen, Tatjana Rundek, Stephen S. Rich, Ruth J. F. Loos, Esteban J. Parra, Miguel Cruz, Jerome I. Rotter, Harold Snieder, Maciej Tomaszewski, Benjamin D. Humphreys and Nora Franceschini ()
Additional contact information
Andrew P. Morris: University of Liverpool
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
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
Susan H. Blanton: University of Miami Miller School of Medicine
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
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
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
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
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
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
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
Stephen S. Rich: University of Virginia School of Medicine
Ruth J. F. Loos: 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
Benjamin D. Humphreys: Washington University School of Medicine
Nora Franceschini: University of North Carolina

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07867-7

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