Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
27588450
TITLE
Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.
ABSTRACT
We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
Copyright 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
DATE PUBLISHED
2016 Sep 1
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2016/02/17
accepted 2016/07/08
entrez 2016/09/03 06:00
pubmed 2016/09/03 06:00
medline 2016/09/03 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Mahajan A Mahajan Anubha A Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Rodan AR Rodan Aylin R AR Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA.
Le TH Le Thu H TH Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Gaulton KJ Gaulton Kyle J KJ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
Haessler J Haessler Jeffrey J Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Stilp AM Stilp Adrienne M AM Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Kamatani Y Kamatani Yoichiro Y Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
Zhu G Zhu Gu G Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
Sofer T Sofer Tamar T Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Puri S Puri Sanjana S Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA.
Schellinger JN Schellinger Jeffrey N JN Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA.
Chu PL Chu Pei-Lun PL Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Cechova S Cechova Sylvia S Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
van Zuydam N van Zuydam Natalie N Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
SUMMIT Consortium
BioBank Japan Project
Arnlov J Arnlov Johan J Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden; School of Health and Social Studies, Dalarna University, Falun 791 88, Sweden.
Flessner MF Flessner Michael F MF National Institute of Diabetes, Digestive, and Kidney Disease, NIH, Bethesda, MD 20892, USA.
Giedraitis V Giedraitis Vilmantas V Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala 752 37, Sweden.
Heath AC Heath Andrew C AC Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
Kubo M Kubo Michiaki M Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
Larsson A Larsson Anders A Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
Lindgren CM Lindgren Cecilia M CM Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7BN, UK.
Madden PA Madden Pamela A F PA Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
Montgomery GW Montgomery Grant W GW Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
Papanicolaou GJ Papanicolaou George J GJ Epidemiology Branch, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
Reiner AP Reiner Alex P AP Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Sundström J Sundström Johan J Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
Thornton TA Thornton Timothy A TA Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Lind L Lind Lars L Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
Ingelsson E Ingelsson Erik E Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala 752 37, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cai J Cai Jianwen J Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Martin NG Martin Nicholas G NG Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
Kooperberg C Kooperberg Charles C Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Matsuda K Matsuda Koichi K Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Whitfield JB Whitfield John B JB Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
Okada Y Okada Yukinori Y Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Laurie CC Laurie Cathy C CC Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Morris AP Morris Andrew P AP Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK. Electronic address: apmorris@liverpool.ac.uk.
Franceschini N Franceschini Nora N Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA. Electronic address: noraf@unc.edu.
INVESTIGATORS
JOURNAL
VOLUME: 99
ISSUE: 3
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2016
MONTH: Sep
DAY: 1
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
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