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.
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Anubha
authors: A
authors: Mahajan
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA.
authors: Aylin R
authors: AR
authors: Rodan
authors: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors: Thu H
authors: TH
authors: Le
authors: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
authors: Kyle J
authors: KJ
authors: Gaulton
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Jeffrey
authors: J
authors: Haessler
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Adrienne M
authors: AM
authors: Stilp
authors: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Yoichiro
authors: Y
authors: Kamatani
authors: Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors: Gu
authors: G
authors: Zhu
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Tamar
authors: T
authors: Sofer
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA.
authors: Sanjana
authors: S
authors: Puri
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75229, USA.
authors: Jeffrey N
authors: JN
authors: Schellinger
authors: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors: Pei-Lun
authors: PL
authors: Chu
authors: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors: Sylvia
authors: S
authors: Cechova
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors: Natalie
authors: N
authors: van Zuydam
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden; School of Health and Social Studies, Dalarna University, Falun 791 88, Sweden.
authors: Johan
authors: J
authors: Arnlov
authors: National Institute of Diabetes, Digestive, and Kidney Disease, NIH, Bethesda, MD 20892, USA.
authors: Michael F
authors: MF
authors: Flessner
authors: Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala 752 37, Sweden.
authors: Vilmantas
authors: V
authors: Giedraitis
authors: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors: Andrew C
authors: AC
authors: Heath
authors: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
authors: Anders
authors: A
authors: Larsson
authors: 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.
authors: Cecilia M
authors: CM
authors: Lindgren
authors: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors: Pamela A F
authors: PAF
authors: Madden
authors: Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors: Grant W
authors: GW
authors: Montgomery
authors: Epidemiology Branch, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
authors: George J
authors: GJ
authors: Papanicolaou
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Alex P
authors: AP
authors: Reiner
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
authors: Johan
authors: J
authors: Sundström
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Timothy A
authors: TA
authors: Thornton
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
authors: Lars
authors: L
authors: Lind
authors: 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.
authors: Erik
authors: E
authors: Ingelsson
authors: Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Jianwen
authors: J
authors: Cai
authors: Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors: Nicholas G
authors: NG
authors: Martin
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Charles
authors: C
authors: Kooperberg
authors: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors: Koichi
authors: K
authors: Matsuda
authors: Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
authors: John B
authors: JB
authors: Whitfield
authors: 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.
authors: Yukinori
authors: Y
authors: Okada
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Cathy C
authors: CC
authors: Laurie
authors: 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.
authors: Andrew P
authors: AP
authors: Morris
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA. Electronic address: noraf@unc.edu.
authors: Nora
authors: N
authors: Franceschini
mesh_terms: D000483:Alleles; D000818:Animals; D003850:Deoxyribonuclease I / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D015810:Linkage Disequilibrium; D008297:Male; D050778:NFATC Transcription Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci; D020710:RGS Proteins / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000503:physiopathology*; D055049:Salt Tolerance / Q000235:genetics; D012965:Sodium Chloride / Q000494:pharmacology*; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects* / Q000235:genetics*
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D020710:RGS Proteins; C491400:RGS14 protein, human; C491399:Rgs14 protein, mouse; C493554:SLC34A1 protein, human; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D012965:Sodium Chloride; D003850:Deoxyribonuclease I