Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.
Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.
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DOI：
10.1016/j.ajhg.2016.07.012
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发表时间：
2016-09-01
影响因子：
9.8
通讯作者：
Franceschini N
中科院分区：
文献类型：
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作者：
Mahajan A;Rodan AR;Le TH;Gaulton KJ;Haessler J;Stilp AM;Kamatani Y;Zhu G;Sofer T;Puri S;Schellinger JN;Chu PL;Cechova S;van Zuydam N;SUMMIT Consortium;BioBank Japan Project;Arnlov J;Flessner MF;Giedraitis V;Heath AC;Kubo M;Larsson A;Lindgren CM;Madden PAF;Montgomery GW;Papanicolaou GJ;Reiner AP;Sundström J;Thornton TA;Lind L;Ingelsson E;Cai J;Martin NG;Kooperberg C;Matsuda K;Whitfield JB;Okada Y;Laurie CC;Morris AP;Franceschini N
我们分析了全基因组关联研究 (GWAS)，包括来自四个祖先的 71,638 名个体的数据，以估计肾小球滤过率 (eGFR)，这是一种用于定义慢性肾病 (CKD) 的肾功能指标。我们确定了 20 个位点，这些位点在全基因组范围内与肾功能相关（p < 5 × 10−8），并强调了先导 SNP 对 eGFR 的等位基因影响在不同祖先中是同质的。我们利用不同群体之间连锁不平衡模式的差异，通过构建驱动 eGFR 关联信号的“可信变体集”来精细绘制 20 个基因座。人肾细胞中 20 个 eGFR 位点的可信变异富含 DNase I 超敏位点 (DHS)。 DHS 可信变异是多个组织中 NFATC1 和 RGS14（位于 SLC34A1 基因座）的表达数量性状位点。果蝇中这两个基因的祖先直系同源物的功能丧失突变与盐胁迫敏感性的改变有关。在盐敏感小鼠模型中，暴露于高盐饮食或诱导 CKD 后，Nfatc1 和 Rgs14 的肾脏 mRNA 表达也会降低。我们的研究 (1) 证明了通过将涉及不同人群的 GWAS 与相关组织的基因组注释相整合来确定关联信号发挥作用的分子机制，从而实现跨种族精细绘图的实用性；(2) 表明盐敏感性可能是影响人类肾功能和 CKD 的生物过程的重要标志。
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.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
9.8
作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
5.5
作者：
通讯作者：
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DOI：
10.1111/dme.12211
发表时间：
2013-10
期刊：
Diabetic medicine : a journal of the British Diabetic Association
影响因子：
--
作者：
Deshmukh HA;Palmer CN;Morris AD;Colhoun HM
通讯作者：
Colhoun HM