New Results
Trans-ethnic genome-wide association study of kidney function provides novel insight into effector genes and causal 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 Arnlov, Susan H Blanton, Martin H de Borst, Erwin P Bottinger, Thomas A Buchanan, Fadi J Charchar, Jeffrey Damman, James Eales, Ali G Gharavi, Vilmantas Giedraitis, Andrew C Heath, Eli Ipp, Krzysztof Kiryluk, Michiaki Kubo, Anders Larsson, Cecilia M Lindgren, Yingchang Lu, Pamela AF Madden, Holly J Mattix-Kramer, Grant W Montgomery, George J Papanicolaou, Leslie J Raffel, Ralph L Sacco, Elena Sanchez, Johan Sundstrom, Kent D Taylor, Anny H Xiang, 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, Tanja Rundek, Stephen S Rich, Ruth JF Loos, Esteban J Parra, Miguel Cruz, Jerome I Rotter, Harold Snieder, Maciej Tomaszewski, Benjamin D Humphreys, Nora Franceschini, on behalf of the Continental Origins and Genetic Epidemiology Network (COGENT) Kidney Consortium
doi: https://doi.org/10.1101/420273
Andrew P Morris
1Department of Biostatistics, University of Liverpool, Liverpool, UK
2Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Thu H Le
3Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, VA, USA
Haojia Wu
4Division of Nephrology, Washington University School of Medicine, St Louis, MO, USA
Artur Akbarov
5Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
Peter J van der Most
6Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Gibran Hemani
7MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK
George Davey Smith
7MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK
Anubha Mahajan
2Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Kyle J Gaulton
8Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
Girish N Nadkarni
9Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
10Division of Nephrology and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Adan Valladares-Salgado
11Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
Niels Wacher-Rodarte
12Unidad de Investigación Médica en Epidemiologia Clinica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
Josyf C Mychaleckyj
13Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA
Nicole D Dueker
14John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Xiuqing Guo
15Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Yang Hai
15Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Jeffrey Haessler
16Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Yoichiro Kamatani
17Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Adrienne M Stilp
18Department of Biostatistics, University of Washington, Seattle, WA, USA
Gu Zhu
19Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
James P Cook
1Department of Biostatistics, University of Liverpool, Liverpool, UK
Johan Arnlov
20Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Huddinge, Sweden
21School of Health and Social Studies, Dalarna University, Falun, Sweden
Susan H Blanton
14John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
22Dr John T Macdonald Department of Human Genetics, University of Miami, Miami, FL, USA
Martin H de Borst
23Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Erwin P Bottinger
9Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Thomas A Buchanan
24Department of Medicine, Endocrine Division, Keck School of Medicine of USC, Los Angeles, CA, USA
Fadi J Charchar
25School of Health and Life Sciences, Federation University Australia, Ballarat, Australia
26Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
Jeffrey Damman
27Department of Pathology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands
James Eales
5Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
Ali G Gharavi
28Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Vilmantas Giedraitis
29Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden
Andrew C Heath
30Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
Eli Ipp
31David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
32Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, USA
Krzysztof Kiryluk
28Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Michiaki Kubo
33Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Anders Larsson
34Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
Cecilia M Lindgren
2Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
35Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
36Broad Institute of Harvard and MIT, Boston, MA, USA
Yingchang Lu
9Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Pamela AF Madden
30Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
Holly J Mattix-Kramer
37Department of Medicine and Nephrology, Loyola University Medical Center, Maywood, IL, USA
Grant W Montgomery
38Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
George J Papanicolaou
39Epidemiology Branch, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD, USA
Leslie J Raffel
40Department of Pediatrics, Division of Genetic and Genomic Medicine, University of California, Irvine, CA, USA
Ralph L Sacco
41Departments of Neurology and Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA
42McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
43Department of Neurology, Jackson Memorial Hospital, University of Miami, Miami, FL, USA
Elena Sanchez
29Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden
Johan Sundstrom
35Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Kent D Taylor
15Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Anny H Xiang
44Department of Research and Education, Kaiser Permanente Southern California, Pasadena, CA, USA
Lars Lind
35Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Erik Ingelsson
45Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
46Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
47Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Nicholas G Martin
19Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
John B Whitfield
19Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Jianwen Cai
48Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Cathy C Laurie
18Department of Biostatistics, University of Washington, Seattle, WA, USA
Yukinori Okada
17Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
49Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
Koichi Matsuda
50Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Charles Kooperberg
16Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Yii-Der Ida Chen
15Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Tanja Rundek
23Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
42McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
Stephen S Rich
13Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA
Ruth JF Loos
9Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
51Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Esteban J Parra
52Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, Canada
Miguel Cruz
11Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
Jerome I Rotter
15Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Harold Snieder
6Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Maciej Tomaszewski
5Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
53Division of Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
Benjamin D Humphreys
4Division of Nephrology, Washington University School of Medicine, St Louis, MO, USA
Nora Franceschini
54Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
Abstract
Chronic kidney disease (CKD) affects ∼10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Posted September 18, 2018.
Trans-ethnic genome-wide association study of kidney function provides novel insight into effector genes and causal 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 Arnlov, Susan H Blanton, Martin H de Borst, Erwin P Bottinger, Thomas A Buchanan, Fadi J Charchar, Jeffrey Damman, James Eales, Ali G Gharavi, Vilmantas Giedraitis, Andrew C Heath, Eli Ipp, Krzysztof Kiryluk, Michiaki Kubo, Anders Larsson, Cecilia M Lindgren, Yingchang Lu, Pamela AF Madden, Holly J Mattix-Kramer, Grant W Montgomery, George J Papanicolaou, Leslie J Raffel, Ralph L Sacco, Elena Sanchez, Johan Sundstrom, Kent D Taylor, Anny H Xiang, 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, Tanja Rundek, Stephen S Rich, Ruth JF Loos, Esteban J Parra, Miguel Cruz, Jerome I Rotter, Harold Snieder, Maciej Tomaszewski, Benjamin D Humphreys, Nora Franceschini, on behalf of the Continental Origins and Genetic Epidemiology Network (COGENT) Kidney Consortium
bioRxiv 420273; doi: https://doi.org/10.1101/420273
Trans-ethnic genome-wide association study of kidney function provides novel insight into effector genes and causal 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 Arnlov, Susan H Blanton, Martin H de Borst, Erwin P Bottinger, Thomas A Buchanan, Fadi J Charchar, Jeffrey Damman, James Eales, Ali G Gharavi, Vilmantas Giedraitis, Andrew C Heath, Eli Ipp, Krzysztof Kiryluk, Michiaki Kubo, Anders Larsson, Cecilia M Lindgren, Yingchang Lu, Pamela AF Madden, Holly J Mattix-Kramer, Grant W Montgomery, George J Papanicolaou, Leslie J Raffel, Ralph L Sacco, Elena Sanchez, Johan Sundstrom, Kent D Taylor, Anny H Xiang, 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, Tanja Rundek, Stephen S Rich, Ruth JF Loos, Esteban J Parra, Miguel Cruz, Jerome I Rotter, Harold Snieder, Maciej Tomaszewski, Benjamin D Humphreys, Nora Franceschini, on behalf of the Continental Origins and Genetic Epidemiology Network (COGENT) Kidney Consortium
bioRxiv 420273; doi: https://doi.org/10.1101/420273
Subject Area
Subject Areas
- Biochemistry (4972)
- Bioengineering (3481)
- Bioinformatics (15203)
- Biophysics (6895)
- Cancer Biology (5388)
- Cell Biology (7738)
- Clinical Trials (138)
- Developmental Biology (4529)
- Ecology (7145)
- Epidemiology (2059)
- Evolutionary Biology (10225)
- Genetics (7511)
- Genomics (9785)
- Immunology (4842)
- Microbiology (13213)
- Molecular Biology (5138)
- Neuroscience (29420)
- Paleontology (203)
- Pathology (836)
- Pharmacology and Toxicology (1463)
- Physiology (2137)
- Plant Biology (4747)
- Synthetic Biology (1338)
- Systems Biology (4012)
- Zoology (768)