Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.
Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.
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DOI：
10.1038/ng.3660
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发表时间：
2016-10
期刊：
影响因子：
30.8
通讯作者：
Chasman DI
中科院分区：
文献类型：
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作者：
Liu C;Kraja AT;Smith JA;Brody JA;Franceschini N;Bis JC;Rice K;Morrison AC;Lu Y;Weiss S;Guo X;Palmas W;Martin LW;Chen YD;Surendran P;Drenos F;Cook JP;Auer PL;Chu AY;Giri A;Zhao W;Jakobsdottir J;Lin LA;Stafford JM;Amin N;Mei H;Yao J;Voorman A;CHD Exome+ Consortium;ExomeBP Consortium;GoT2DGenes Consortium;T2D-GENES Consortium;Larson MG;Grove ML;Smith AV;Hwang SJ;Chen H;Huan T;Kosova G;Stitziel NO;Kathiresan S;Samani N;Schunkert H;Deloukas P;Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia;Li M;Fuchsberger C;Pattaro C;Gorski M;CKDGen Consortium;Kooperberg C;Papanicolaou GJ;Rossouw JE;Faul JD;Kardia SL;Bouchard C;Raffel LJ;Uitterlinden AG;Franco OH;Vasan RS;O'Donnell CJ;Taylor KD;Liu K;Bottinger EP;Gottesman O;Daw EW;Giulianini F;Ganesh S;Salfati E;Harris TB;Launer LJ;Dörr M;Felix SB;Rettig R;Völzke H;Kim E;Lee WJ;Lee IT;Sheu WH;Tsosie KS;Edwards DR;Liu Y;Correa A;Weir DR;Völker U;Ridker PM;Boerwinkle E;Gudnason V;Reiner AP;van Duijn CM;Borecki IB;Edwards TL;Chakravarti A;Rotter JI;Psaty BM;Loos RJ;Fornage M;Ehret GB;Newton-Cheh C;Levy D;Chasman DI
使用以外显子组为中心的单变体和基于基因的测试对血压关联结果进行荟萃分析，在 146,562 名个体中发现了 31 个新位点，并对另外 180,726 名个体进行了随访和荟萃分析（Ntotal=327,288）。这些血压基因座富含已知的心脏代谢特征变异。还观察到 NPR1、DBH 和 PTPMT1 三个基因中罕见/低频错义变异聚集的关联。此外，先前报道的 39 个基因座的血压关联性也得到了证实。已确定的变异涉及与心脏代谢特征、血管功能和发育相关的生物途径。一些新的变体被推断在转录中发挥作用或作为蛋白质-蛋白质相互作用网络的枢纽。根据已识别的变异构建的遗传风险评分与冠心病和心肌梗塞密切相关。大量血压基因座的收集提出了新的高血压治疗策略，强调与心脏代谢风险的联系。
Meta-analyses of association results for blood pressure using exome-centric single-variants and gene-based tests identified 31 novel loci in discovery among 146,562 individuals with follow-up and meta-analysis in 180,726 additional individuals (Ntotal=327,288). These blood pressure loci are enriched for known cardiometabolic trait variants. Associations were also observed for the aggregation of rare/low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure loci suggests new therapeutic strategies for hypertension emphasizing a link with cardiometabolic risk.