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Nat Commun. 2019 Jan 3;10(1):29. doi: 10.1038/s41467-018-07867-7.

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

Author information

1
Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK. apmorris@liverpool.ac.uk.
2
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. apmorris@liverpool.ac.uk.
3
Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, VA, 22908, USA.
4
Division of Nephrology, Washington University School of Medicine, St Louis, MO, 63110, USA.
5
Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, M13 9PT, UK.
6
Department of Epidemiology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, Netherlands.
7
MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, BS8 1TH, UK.
8
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
9
Department of Pediatrics, University of California, San Diego, San Diego, CA, 92161, USA.
10
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
11
Division of Nephrology and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12
Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico.
13
Unidad de Investigación Médica en Epidemiologia Clinica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, 06720, Mexico.
14
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
15
John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33124, USA.
16
Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
17
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
18
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
19
Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
20
Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
21
Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK.
22
Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Huddinge, 141 83, Sweden.
23
School of Health and Social Studies, Dalarna University, Falun, 791 88, Sweden.
24
Dr John T Macdonald Department of Human Genetics, University of Miami, Miami, FL, 33124, USA.
25
Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, Netherlands.
26
Department of Medicine, Division of Endocrinology and Diabetes, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
27
School of Health and Life Sciences, Federation University Australia, Ballarat, VIC, 3350, Australia.
28
Department of Cardiovascular Sciences, University of Leicester, Leicester, LE1 7RH, UK.
29
Department of Physiology, University of Melbourne, Parkville, VIC, 3010, Australia.
30
Department of Internal Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan.
31
Department of Pathology, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
32
Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
33
Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, 751 85, Sweden.
34
Department of Psychiatry, Washington University in St Louis, St Louis, MO, 63110, USA.
35
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90024, USA.
36
Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA, 90502, USA.
37
Department of Medicine and Nephrology, Loyola University Medical Center, Maywood, IL, 60153, USA.
38
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
39
Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, 751 85, Sweden.
40
Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
41
Broad Institute of Harvard and MIT, Boston, MA, 02142, USA.
42
Brisbane Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia.
43
Epidemiology Branch, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD, 20892, USA.
44
Department of Pediatrics, Division of Genetic and Genomic Medicine, University of California, Irvine Orange, CA, 92868, USA.
45
Departments of Neurology and Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
46
Evelyn F McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
47
Jackson Memorial Hospital, University of Miami, Miami, FL, 33136-1096, USA.
48
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, 40225, Germany.
49
Department of Research and Education, Kaiser Permanente Southern California, Pasadena, CA, 91101, USA.
50
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94309, USA.
51
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94309, USA.
52
Stanford Diabetes Research Center, Stanford University, Stanford, CA, 94305, USA.
53
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, 751 85, Sweden.
54
Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7420, USA.
55
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Suita, 565-0871, Japan.
56
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
57
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
58
Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, L5L 1C6, Canada.
59
Division of Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
60
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27516-8050, USA. noraf@unc.edu.

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.

PMID:
30604766
PMCID:
PMC6318312
DOI:
10.1038/s41467-018-07867-7
[Indexed for MEDLINE]
Free PMC Article

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