Stroke genetics informs drug discovery and risk prediction across ancestries.
Stroke genetics informs drug discovery and risk prediction across ancestries.
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DOI：
10.1038/s41586-022-05165-3
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发表时间：
2022-11
期刊：
影响因子：
64.8
通讯作者：
Gravel, Simon
中科院分区：
文献类型：
--
作者：
Mishra, Aniket;Malik, Rainer;Hachiya, Tsuyoshi;Jurgenson, Tuuli;Namba, Shinichi;Posner, Daniel C.;Kamanu, Frederick K.;Koido, Masaru;Le Grand, Quentin;Shi, Mingyang;He, Yunye;Georgakis, Marios K.;Caro, Ilana;Krebs, Kristi;Liaw, Yi-Ching;Vaura, Felix C.;Lin, Kuang;Winsvold, Bendik Slagsvold;Srinivasasainagendra, Vinodh;Parodi, Livia;Bae, Hee-Joon;Chauhan, Ganesh;Chong, Michael R.;Tomppo, Liisa;Akinyemi, Rufus;Roshchupkin, Gennady V.;Habib, Naomi;Jee, Yon Ho;Thomassen, Jesper Qvist;Abedi, Vida;Carcel-Marquez, Jara;Nygaard, Marianne;Leonard, Hampton L.;Yang, Chaojie;Yonova-Doing, Ekaterina;Knol, Maria J.;Lewis, Adam J.;Judy, Renae L.;Ago, Tetsuro;Amouyel, Philippe;Armstrong, Nicole D.;Bakker, Mark K.;Bartz, Traci M.;Bennett, David A.;Bis, Joshua C.;Bordes, Constance;Borte, Sigrid;Cain, Anael;Ridker, Paul M.;Cho, Kelly;Chen, Zhengming;Cruchaga, Carlos;Cole, John W.;de Jager, Phil L.;de Cid, Rafael;Endres, Matthias;Ferreira, Leslie E.;Geerlings, Mirjam I.;Gasca, Natalie C.;Gudnason, Vilmundur;Hata, Jun;He, Jing;Heath, Alicia K.;Ho, Yuk-Lam;Havulinna, Aki S.;Hopewell, Jemma C.;Hyacinth, Hyacinth I.;Inouye, Michael;Jacob, Mina A.;Jeon, Christina E.;Jern, Christina;Kamouchi, Masahiro;Keene, Keith L.;Kitazono, Takanari;Kittner, Steven J.;Konuma, Takahiro;Kumar, Amit;Lacaze, Paul;Launer, Lenore J.;Lee, Keon-Joo;Lepik, Kaido;Li, Jiang;Li, Liming;Manichaikul, Ani;Markus, Hugh S.;Marston, Nicholas A.;Meitinger, Thomas;Mitchell, Braxton D.;Montellano, Felipe A.;Morisaki, Takayuki;Mosley, Thomas H.;Nalls, Mike A.;Nordestgaard, Borge G.;O'Donnell, Martin J.;Okada, Yukinori;Onland-Moret, N. Charlotte;Ovbiagele, Bruce;Peters, Annette;Psaty, Bruce M.;Rich, Stephen S.;Rosand, Jonathan;Sabatine, Marc S.;Sacco, Ralph L.;Saleheen, Danish;Sandset, Else Charlotte;Salomaa, Veikko;Sargurupremraj, Muralidharan;Sasaki, Makoto;Satizabal, Claudia L.;Schmidt, Carsten O.;Shimizu, Atsushi;Smith, Nicholas L.;Sloane, Kelly L.;Sutoh, Yoichi;Sun, Yan V.;Tanno, Kozo;Tiedt, Steffen;Tatlisumak, Turgut;Torres-Aguila, Nuria P.;Tiwari, Hemant K.;Tregouet, David-Alexandre;Trompet, Stella;Tuladhar, Anil Man;Tybjaerg-Hansen, Anne;van Vugt, Marion;Vibo, Riina;Verma, Shefali S.;Wiggins, Kerri L.;Wennberg, Patrik;Woo, Daniel;Wilson, Peter W. F.;Xu, Huichun;Yang, Qiong;Yoon, Kyungheon;Millwood, Iona Y.;Gieger, Christian;Ninomiya, Toshiharu;Grabe, Hans J.;Jukema, J. Wouter;Rissanen, Ina L.;Strbian, Daniel;Kim, Young Jin;Chen, Pei-Hsin;Mayerhofer, Ernst;Howson, Joanna M. M.;Irvin, Marguerite R.;Adams, Hieab;Wassertheil-Smoller, Sylvia;Christensen, Kaare;Ikram, Mohammad A.;Rundek, Tatjana;Worrall, Bradford B.;Lathrop, G. Mark;Riaz, Moeen;Simonsick, Eleanor M.;Korv, Janika;Franca, Paulo H. C.;Zand, Ramin;Prasad, Kameshwar;Frikke-Schmidt, Ruth;de Leeuw, Frank-Erik;Liman, Thomas;Haeusler, Karl Georg;Ruigrok, Ynte M.;Heuschmann, Peter Ulrich;Longstreth, W. T.;Jung, Keum Ji;Bastarache, Lisa;Pare, Guillaume;Damrauer, Scott M.;Chasman, Daniel I.;Rotter, Jerome I.;Anderson, Christopher D.;Zwart, John-Anker;Niiranen, Teemu J.;Fornage, Myriam;Liaw, Yung-Po;Seshadri, Sudha;Fernandez-Cadenas, Israel;Walters, Robin G.;Ruff, Christian T.;Owolabi, Mayowa O.;Huffman, Jennifer E.;Milani, Lili;Kamatani, Yoichiro;Dichgans, Martin;Debette, Stephanie;Lee, Jin-Moo;Cheng, Yu-Ching;Meschia, James F.;Chen, Wei Min;Sale, Michele M.;Zonderman, Alan B.;Evans, Michele K.;Wilson, James G.;Correa, Adolfo;Traylor, Matthew;Lewis, Cathryn M.;Reiner, Alexander;Haessler, Jeffrey;Langefeld, Carl D.;Gottesman, Rebecca F.;Yaffe, Kristine;Liu, Yong Mei;Kooperberg, Charles;Lange, Leslie A.;Furie, Karen L.;Arnett, Donna K.;Benavente, Oscar R.;Grewal, Raji P.;Peddareddygari, Leema Reddy;Hveem, Kristian;Lindstrom, Sara;Wang, Lu;Smith, Erin N.;Gordon, William;Vlieg, Astrid van Hylckama;de Andrade, Mariza;Brody, Jennifer A.;Pattee, Jack W.;Brumpton, Ben M.;Suchon, Pierre;Chen, Ming-Huei;Frazer, Kelly A.;Turman, Constance;Germain, Marine;MacDonald, James;Braekkan, Sigrid K.;Armasu, Sebastian M.;Pankratz, Nathan;Jackson, Rebecca D.;Nielsen, Jonas B.;Giulianin, Franco;Puurunen, Marja K.;Ibrahim, Manal;Heckbert, Susan R.;Bammler, Theo K.;McCauley, Bryan M.;Taylor, Kent D.;Pankow, James S.;Reiner, Alexander P.;Gabrielsen, Maiken E.;Deleuze, Jean-Francois;O'Donnell, Chris J.;Kim, Jihye;McKnight, Barbara;Kraft, Peter;Hansen, John-Bjarne;Rosendaal, Frits R.;Heit, John A.;Tang, Weihong;Morange, Pierre-Emmanuel;Johnson, Andrew D.;Kabrhel, Christopher;van Dijk, Ewoud J.;Koudstaal, Peter J.;Luijckx, Gert-Jan;Nederkoorn, Paul J.;van Oostenbrugge, Robert J.;Visser, Marieke C.;Wermer, Marieke J. H.;Kappelle, L. Jaap;Esko, Tonu;Metspalu, Andres;Magi, Reedik;Nelis, Mari;Levi, Christopher R.;Maguire, Jane;Jimenez-Conde, Jordi;Sharma, Pankaj;Sudlow, Cathie L. M.;Rannikmae, Kristiina;Schmidt, Reinhold;Slowik, Agnieszka;Pera, Joanna;Thijs, Vincent N. S.;Lindgren, Arne G.;Ilinca, Andreea;Melander, Olle;Engstrom, Gunnar;Rexrode, Kathryn M.;Rothwell, Peter M.;Stanne, Tara M.;Johnson, Julie A.;Danesh, John;Butterworth, Adam S.;Heitsch, Laura;Boncoraglio, Giorgio B.;Kubo, Michiaki;Pezzini, Alessandro;Rolfs, Arndt;Giese, Anne-Katrin;Weir, David;Ross, Owen A.;Lemmons, Robin;Soderholm, Martin;Cushman, Mary;Jood, Katarina;McDonough, Caitrin W.;Bell, Steven;Linkohr, Birgit;Lee, Tsong-Hai;Putaala, Jukka;Lopez, Oscar L.;Carty, Cara L.;Jian, Xueqiu;Schminke, Ulf;Cullell, Natalia;Delgado, Pilar;Ibanez, Laura;Krupinski, Jerzy;Lioutas, Vasileios;Matsuda, Koichi;Montaner, Joan;Muino, Elena;Roquer, Jaume;Sarnowski, Chloe;Sattar, Naveed;Sibolt, Gerli;Teumer, Alexander;Rutten-Jacobs, Loes;Kanai, Masahiro;Gretarsdottir, Solveig;Rost, Natalia S.;Yusuf, Salim;Almgren, Peter;Ay, Hakan;Bevan, Steve;Brown, Robert D., Jr.;Carrera, Caty;Buring, Julie E.;Chen, Wei-Min;Cotlarciuc, Ioana;de Bakker, Paul I. W.;DeStefano, Anita L.;den Hoed, Marcel;Duan, Qing;Engelter, Stefan T.;Falcone, Guido J.;Gustafsson, Stefan;Hassan, Ahamad;Holliday, Elizabeth G.;Howard, George;Hsu, Fang-Chi;Ingelsson, Erik;Harris, Tamara B.;Kissela, Brett M.;Kleindorfer, Dawn O.;Langenberg, Claudia;Leys, Didier;Lin, Wei-Yu;Lorentzen, Erik;Magnusson, Patrik K.;McArdle, Patrick F.;Pulit, Sara L.;Rice, Kenneth;Sakaue, Saori;Sapkota, Bishwa R.;Tanislav, Christian;Thorleifsson, Gudmar;Thorsteinsdottir, Unnur;Tzourio, Christophe;van Duijn, Cornelia M.;Walters, Matthew;Wareham, Nicholas J.;Amin, Najaf;Aparicio, Hugo J.;Attia, John;Beiser, Alexa S.;Berr, Claudine;Bustamante, Mariana;Caso, Valeria;Choi, Seung Hoan;Chowhan, Ayesha;Dartigues, Jean-Francois;Delavaran, Hossein;Dorr, Marcus;Ford, Ian;Gurpreet, Wander S.;Hamsten, Anders;Hozawa, Atsushi;Ingelsson, Martin;Iwasaki, Motoki;Kaffashian, Sara;Kalra, Lalit;Kjartansson, Olafur;Kloss, Manja;Labovitz, Daniel L.;Laurie, Cathy C.;Li, Linxin;Lind, Lars;Lindgren, Cecilia M.;Makoto, Hirata;Minegishi, Naoko;Morris, Andrew P.;Mueller-Nurasyid, Martina;Norrving, Bo;Ogishima, Soichi;Parati, Eugenio A.;Pedersen, Nancy L.;Perola, Markus;Jousilahti, Pekka;Pileggi, Silvana;Rabionet, Raquel;Riba-Llena, Iolanda;Ribases, Marta;Romero, Jose R.;Rudd, Anthony G.;Sarin, Antti-Pekka;Sarju, Ralhan;Satoh, Mamoru;Sawada, Norie;Sigurdsson, Asgeir;Smith, Albert;Stine, O. Colin;Stott, David J.;Strauch, Konstantin;Takai, Takako;Tanaka, Hideo;Touze, Emmanuel;Tsugane, Shoichiro;Uitterlinden, Andre G.;Valdimarsson, Einar M.;van der Lee, Sven J.;Wakai, Kenji;Williams, Stephen R.;Wolfe, Charles D. A.;Wong, Quenna;Yamaji, Taiki;Sanghera, Dharambir K.;Stefansson, Kari;Martinez-Majander, Nicolas;Sobue, Kenji;Soriano-Tarraga, Carolina;Volzke, Henry;Akpa, Onoja;Sarfo, Fred S.;Akpalu, Albert;Obiako, Reginald;Wahab, Kolawole;Osaigbovo, Godwin;Owolabi, Lukman;Komolafe, Morenikeji;Jenkins, Carolyn;Arulogun, Oyedunni;Ogbole, Godwin;Adeoye, Abiodun M.;Akinyemi, Joshua;Agunloye, Atinuke;Fakunle, Adekunle G.;Uvere, Ezinne;Olalere, Abimbola;Adebajo, Olayinka J.;Chen, Junshi;Clarke, Robert;Collins, Rory;Guo, Yu;Wang, Chen;Lv, Jun;Peto, Richard;Chen, Yiping;Fairhurst-Hunter, Zammy;Hill, Michael;Pozarickij, Alfred;Schmidt, Dan;Stevens, Becky;Turnbull, Iain;Yu, Canqing;Nagai, Akiko;Murakami, Yoishinori;Shiroma, Eric J.;Sigurdsson, Sigurdur;Ghanbari, Mohsen;Boerwinkle, Eric;Fongang, Bernard;Wang, Ruiqi;Ikram, Mohammad K.;Volker, Uwe;de Laat, Karlijn F.;van Norden, Anouk G. W.;de Kort, Paul L.;Vermeer, Sarah E.;Brouwers, Paul J. A. M.;Gons, Rob A. R.;den Heijer, Tom;van Dijk, Gert W.;van Rooij, Frank G. W.;Aamodt, Anne H.;Skogholt, Anne H.;Willer, Cristen J.;Heuch, Ingrid;Hagen, Knut;Fritsche, Lars G.;Pedersen, Linda M.;Ellekjaer, Hanne;Zhou, Wei;Martinsen, Amy E.;Kristoffersen, Espen S.;Thomas, Laurent F.;Kleinschnitz, Christoph;Frantz, Stefan;Ungethum, Kathrin;Gallego-Fabrega, Cristina;Lledos, Miquel;Llucia-Carol, Laia;Sobrino, Tomas;Campos, Francisco;Castillo, Jose;Freijo, Marimar;Arenillas, Juan Francisco;Obach, Victor;Alvarez-Sabin, Jose;Molina, Carlos A.;Ribo, Marc;Munoz-Narbona, Lucia;Lopez-Cancio, Elena;Millan, Monica;Diaz-Navarro, Rosa;Vives-Bauza, Cristofol;Serrano-Heras, Gemma;Segura, Tomas;Dhar, Rajat;Delgado-Mederos, Raquel;Prats-Sanchez, Luis;Camps-Renom, Pol;Blay, Natalia;Sumoy, Lauro;Marti-Fabregas, Joan;Schnohr, Peter;Jensen, Gorm B.;Benn, Marianne;Afzal, Shoaib;Kamstrup, Pia R.;van Setten, Jessica;van der Laan, Sander W.;Vonk, Jet M. J.;Kim, Bong-Jo;Curtze, Sami;Tiainen, Marjaana;Kinnunen, Janne;Menon, Vilas;Sung, Yun Ju;Yang, Chengran;Saillour-Glenisson, Florence;Gravel, Simon
中风是全球第二大死亡原因，以前的全基因组关联研究（GWASs）主要是在欧洲血统人群中进行的。在对110,182例卒中患者（5个祖先，33%非欧洲人）和1,503,898名对照个体的跨祖先GWAS荟萃分析中，我们在89个（61个新的）独立基因座中发现了卒中及其亚型的关联信号：60个在初级反方差加权分析中，29个在次级荟萃回归和多性状分析中。基于内部交叉祖先验证和对89084例卒中病例（30%非欧洲人）和1013843例对照个体的独立随访，87%的原发性卒中危险基因位点和60%的继发性卒中危险基因位点被重复（P < 0.05）。不同祖先的效应值高度相关。跨祖先精细定位、计算机突变分析、转录组和蛋白质组关联分析揭示了推定的致病基因（如SH3PXD2A和FURIN）和变异（如GRK5和NOS3）。采用三管齐下的方法，我们为假定的药物效应提供了遗传证据，强调F11、KLKB1、PROC、GP1BA、LAMC2和VCAM1是可能的靶点，目前已经在研究F11和PROC治疗中风的药物。多基因评分将跨祖先和祖先特异性中风GWASs与血管危险因子GWASs（综合多基因评分）结合起来，有力地预测了欧洲、东亚和非洲血统人群的缺血性中风。在52,600名患有心脏代谢疾病的临床试验参与者中，卒中遗传风险评分可预测独立于临床危险因素的缺血性卒中。我们的研究结果为生物学提供了信息，揭示了潜在的药物靶点，并获得了跨祖先遗传风险预测工具。一项全基因组关联研究的跨祖先meta分析确定了89个（61个新的）独立基因座与脑卒中及其亚型的关联信号，揭示了可能的致病基因，强调F11、KLKB1、PROC、GP1BA、LAMC2和VCAM1是潜在的药物靶点，并提供了跨祖先综合风险预测。
Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries. A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.
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影响因子：
3.7
作者：
Safdar H;Cleuren AC;Cheung KL;Gonzalez FJ;Vos HL;Inoue Y;Reitsma PH;van Vlijmen BJ
通讯作者：
van Vlijmen BJ
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
4.5
作者：
Feng H;Mancuso N;Gusev A;Majumdar A;Major M;Pasaniuc B;Kraft P
通讯作者：
Kraft P
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ