Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity

the SUMMIT Consortium, the BioBank Japan Project

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)636-646
Number of pages11
JournalAmerican Journal of Human Genetics
Volume99
Issue number3
DOIs
Publication statusPublished - 01-09-2016

Fingerprint

Glomerular Filtration Rate
Salts
Kidney
Chronic Renal Insufficiency
Genes
Genome-Wide Association Study
Deoxyribonuclease I
Hypersensitivity
Biological Phenomena
Metagenomics
Quantitative Trait Loci
Linkage Disequilibrium
Drosophila melanogaster
Single Nucleotide Polymorphism
Genome
Diet
Messenger RNA
Mutation
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

the SUMMIT Consortium ; the BioBank Japan Project. / Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 3. pp. 636-646.
@article{0bfe551b7470498ca59213dcc0178514,
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.",
author = "{the SUMMIT Consortium} and {the BioBank Japan Project} and Anubha Mahajan and Rodan, {Aylin R R.} and Le, {Thu H H.} and Gaulton, {Kyle J J.} and Jeffrey Haessler and Stilp, {Adrienne M M.} and Yoichiro Kamatani and Gu Zhu and Tamar Sofer and Sanjana Puri and Schellinger, {Jeffrey N N.} and Chu, {Pei Lun} and Sylvia Cechova and Natalie van Zuydam and Johan Arnlov and Flessner, {Michael F F.} and Vilmantas Giedraitis and Heath, {Andrew C C.} and Michiaki Kubo and Anders Larsson and Lindgren, {Cecilia M M.} and Madden, {Pamela A A.F.} and Montgomery, {Grant W W.} and Papanicolaou, {George J J.} and Reiner, {Alex P P.} and Johan Sundstr{\"o}m and Thornton, {Timothy A A.} and Lars Lind and Erik Ingelsson and Jianwen Cai and Martin, {Nicholas G G.} and Charles Kooperberg and Koichi Matsuda and Whitfield, {John B B.} and Yukinori Okada and Laurie, {Cathy C C.} and Morris, {Andrew P P.} and Nora Franceschini",
year = "2016",
month = "9",
day = "1",
doi = "10.1016/j.ajhg.2016.07.012",
language = "English",
volume = "99",
pages = "636--646",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity. / the SUMMIT Consortium; the BioBank Japan Project.

In: American Journal of Human Genetics, Vol. 99, No. 3, 01.09.2016, p. 636-646.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity

AU - the SUMMIT Consortium

AU - the BioBank Japan Project

AU - Mahajan, Anubha

AU - Rodan, Aylin R R.

AU - Le, Thu H H.

AU - Gaulton, Kyle J J.

AU - Haessler, Jeffrey

AU - Stilp, Adrienne M M.

AU - Kamatani, Yoichiro

AU - Zhu, Gu

AU - Sofer, Tamar

AU - Puri, Sanjana

AU - Schellinger, Jeffrey N N.

AU - Chu, Pei Lun

AU - Cechova, Sylvia

AU - van Zuydam, Natalie

AU - Arnlov, Johan

AU - Flessner, Michael F F.

AU - Giedraitis, Vilmantas

AU - Heath, Andrew C C.

AU - Kubo, Michiaki

AU - Larsson, Anders

AU - Lindgren, Cecilia M M.

AU - Madden, Pamela A A.F.

AU - Montgomery, Grant W W.

AU - Papanicolaou, George J J.

AU - Reiner, Alex P P.

AU - Sundström, Johan

AU - Thornton, Timothy A A.

AU - Lind, Lars

AU - Ingelsson, Erik

AU - Cai, Jianwen

AU - Martin, Nicholas G G.

AU - Kooperberg, Charles

AU - Matsuda, Koichi

AU - Whitfield, John B B.

AU - Okada, Yukinori

AU - Laurie, Cathy C C.

AU - Morris, Andrew P P.

AU - Franceschini, Nora

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85020917020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020917020&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.07.012

DO - 10.1016/j.ajhg.2016.07.012

M3 - Article

C2 - 27588450

AN - SCOPUS:85020917020

VL - 99

SP - 636

EP - 646

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -