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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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