Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting. (29th January 2019)

• Record Type: Journal Article
• Authors: Chauhan, Ganesh; Adams, Hieab H.H.; Satizabal, Claudia L.; Bis, Joshua C.; Teumer, Alexander; Sargurupremraj, Muralidharan; Hofer, Edith; Trompet, Stella; Hilal, Saima; Smith, Albert Vernon; Jian, Xueqiu; Malik, Rainer; Traylor, Matthew; Pulit, Sara L.; Amouyel, Philippe; Mazoyer, Bernard; Zhu, Yi-Cheng; Kaffashian, Sara; Schilling, Sabrina; Beecham, Gary W.; Montine, Thomas J.; Schellenberg, Gerard D.; Kjartansson, Olafur; Guðnason, Vilmundur; Knopman, David S.; Griswold, Michael E.; Windham, B. Gwen; Gottesman, Rebecca F.; Mosley, Thomas H.; Schmidt, Reinhold; Saba, Yasaman; Schmidt, Helena; Takeuchi, Fumihiko; Yamaguchi, Shuhei; Nabika, Toru; Kato, Norihiro; Rajan, Kumar B.; Aggarwal, Neelum T.; De Jager, Philip L.; Evans, Denis A.; Psaty, Bruce M.; Rotter, Jerome I.; Rice, Kenneth; Lopez, Oscar L.; Liao, Jiemin; Chen, Christopher; Cheng, Ching-Yu; Wong, Tien Y.; Ikram, Mohammad K.; van der Lee, Sven J.; Amin, Najaf; Chouraki, Vincent; DeStefano, Anita L.; Aparicio, Hugo J.; Romero, Jose R.; Maillard, Pauline; DeCarli, Charles; Wardlaw, Joanna M.; Hernández, Maria del C. Valdés; Luciano, Michelle; Liewald, David; Deary, Ian J.; Starr, John M.; Bastin, Mark E.; Muñoz Maniega, Susana; Slagboom, P. Eline; Beekman, Marian; Deelen, Joris; Uh, Hae-Won; Lemmens, Robin; Brodaty, Henry; Wright, Margaret J.; Ames, David; Boncoraglio, Giorgio B.; Hopewell, Jemma C.; Beecham, Ashley H.; Blanton, Susan H.; Wright, Clinton B.; Sacco, Ralph L.; Wen, Wei; Thalamuthu, Anbupalam; Armstrong, Nicola J.; Chong, Elizabeth; Schofield, Peter R.; Kwok, John B.; van der Grond, Jeroen; Stott, David J.; Ford, Ian; Jukema, J. Wouter; Vernooij, Meike W.; Hofman, Albert; Uitterlinden, André G.; van der Lugt, Aad; Wittfeld, Katharina; Grabe, Hans J.; Hosten, Norbert; von Sarnowski, Bettina; Völker, Uwe; Levi, Christopher; Jimenez-Conde, Jordi; Sharma, Pankaj; Sudlow, Cathie L.M.; Rosand, Jonathan; Woo, Daniel; Cole, John W.; Meschia, James F.; Slowik, Agnieszka; Thijs, Vincent; Lindgren, Arne; Melander, Olle; Grewal, Raji P.; Rundek, Tatjana; Rexrode, Kathy; Rothwell, Peter M.; Arnett, Donna K.; Jern, Christina; Johnson, Julie A.; Benavente, Oscar R.; Wasssertheil-Smoller, Sylvia; Lee, Jin-Moo; Wong, Quenna; Mitchell, Braxton D.; Rich, Stephen S.; McArdle, Patrick F.; Geerlings, Mirjam I.; van der Graaf, Yolanda; de Bakker, Paul I.W.; Asselbergs, Folkert W.; Srikanth, Velandai; Thomson, Russell; McWhirter, Rebekah; Moran, Chris; Callisaya, Michele; Phan, Thanh; Rutten-Jacobs, Loes C.A.; Bevan, Steve; Tzourio, Christophe; Mather, Karen A.; Sachdev, Perminder S.; van Duijn, Cornelia M.; Worrall, Bradford B.; Dichgans, Martin; Kittner, Steven J.; Markus, Hugh S.; Ikram, Mohammad A.; Fornage, Myriam; Launer, Lenore J.; Seshadri, Sudha; Longstreth, W.T.; Debette, Stéphanie; Almgren, Peter; Anderson, Christopher D.; Arnett, Donna K.; Attia, John; Ay, Hakan; Benavente, Oscar R.; Bevan, Steve; Brown, Robert D.; Bustamante, Mariana; Cheng, Yu-Ching; Cole, John W.; Cotlarciuc, Ioana; Cruchaga, Carlos; de Bakker, Paul IW.; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Fornage, Myriam; Grewal, Raji P.; Heitsch, Laura; Holliday, Elizabeth; Ibanez, Laure; Ilinca, Andreea; Irvin, Marguerite R.; Jackson, Rebecca D.; Jern, Christina; Jimenez-Conde, Jordi; Johnson, Julie A.; Jood, Katarina; Kissela, Brett M.; Kittner, Steven J.; Kleindorfer, Dawn O.; Labovitz, Daniel; Laurie, Cathy C.; Lee, Jin-Moo; Lemmens, Robin; Levi, Christopher; Li, Linxin; Lindgren, Arne G.; Maguire, Jane; Markus, Hugh S.; McArdle, Patrick F.; Melander, Olle; Meschia, James F.; Mitchell, Braxton D.; Müller-Nurasyid, Martina; Norrving, Bo; Peddareddygari, Leema Reddy; Pera, Joanna; Pulit, Sara L.; Rexrode, Kathryn; Ribasés, Marta; Roquer, Jaume; Rost, Natalia S.; Rothwell, Peter M.; Rundek, Tatjana; Sacco, Ralph L.; Schmidt, Reinhold; Sharma, Pankaj; Slowik, Agnieszka; Soriano-Tárraga, Carolina; Stanne, Tara; Stauch, Konstantin; Stine, O C.; Sudlow, Cathie LM.; Thijs, Vincent N.S.; Wasssertheil-Smoller, Sylvia; Weir, David; Williams, Stephen R.; Wong, Quenna; Woo, Daniel; Worrall, Bradford B.; Xu, Huichun; Seshadri, Sudha; Hyacinth, Hyacinth I; Marini, Sandro; Nyquist, Paul; Lewis, Cathryn; Hansen, Bjorn; Norrving, Bo; Rosand, Jonathan; Biffi, Alessandro; Kourkoulis, Christina; Anderson, Chris; Giese, Anne-Katrin; Sacco, Ralph; Sharma, Pankaj; Chung, Jong-Won; Kim, Gyeong-Moon; Lubitz, Steven; Bourcier, Romain; Howson, Joanna; Granata, Alessandra; Drazyk, Anna; Markus, Hugh; Wardlaw, Joanna; Mitchell, Braxton; Cole, John; Hopewell, Jemma; Walters, Robin; Turnbull, Iain; Worrall, Bradford; Bis, Josh; Reiner, Alex; Dhar, Raj; Heitsch, Laura; Lee, Jin-Moo; Prasad, Kameshwar; Sarnowski, Chloé; Aparicio, Hugo Javier; Yang, Qiong; Chasman, Daniel; Rexrode, Kathryn; Phuah, Chia-Ling; Liu, Guiyou; Elkind, Mitchell; Lange, Leslie; Rost, Natalia; James, Michael; Stewart, Jill; Vojinovic, Dina; Thijs, Vincent; Parati, Eugenio; Boncoraglio, Giorgio; Zand, Ramin; Bijlenga, Philippe; Selim, Magdy; Grond-Ginsbach, Caspar; Strbian, Daniel; Tomppo, Liisa; Sallinen, Hanne; Pfeiffer, Dorothea; Torres, Nuria; Barboza, Miguel; Laarman, Melanie; Carriero, Roberta; Holliday, Elizabeth; Jimenez-Conde, Jordi; Soriano, Carolina; Gill, Dipender; Debette, Stephanie; Mishra, Aniket; Wu, Jer-Yuarn; Ko, Tai-Ming; Bione, Silvia; Jood, Katarina; Tatlisumak, Turgut; Holmegaard, Lukas; Yue, Suo; bersano, Anna; Pera, Joanna; Slowik, Agnieszka; Levi, Christopher; Schlicht, Kristina; Lemmens, Robin; Ninomiya, Toshiharu; Oberstein, Saskia Lesnik; Lee, Tsong-Hai; Malik, Rainer; Dichgans, Martin; Lindgren, Arne; Wasselius, Johan; Drake, Mattias; Melander, Olle; Stenman, Martin; Ilinca, Andreea; Crawford, Katherine; Lena, Umme; Mateen, Farrah; Ay, Hakan; Wu, Ona; Schirmer, Markus; Cramer, Steve; Golland, Polina; Brown, Robert; Meschia, James; Ross, Owen A.; Pare, Guillaume; Chong, Mike; Rundek, Tatjana; Gwinn, Katrina; Chen, Christopher; Koenig, Jim; Giralt, Eva; Saleheen, Danish; de Leeuw, Frank-Erik; Klijn, Karin; Kamatani, Yoichiro; Kubo, Michiaki; Okada, Yukinori; Pedersen, Annie; Olsson, Maja; Martín, Juan José; Xu, Huichun; Tan, Eng King; Frid, Petrea; Lee, Chaeyoung; Tregouet, David; Leung, Thomas; Choy, Richard; Jern, Christina; Loo, Keat Wei; Rinkel, Gabriel; Franca, Paulo; Cendes, Iscia; Carrera, Caty; Fernandez-Cadenas, Israel; Montaner, Joan; Kim, Helen; Owolabi, Mayowa; Sofat, Reecha; Bakker, Mark; Ruigrok, Ynte; Hauer, Allard; Pulit, Sara L.; van der Laan, Sander W.; Irvin, Ryan; Sargurupremraj, Murali; Pezzini, Alessandro; Abd-Allah, Foad; Liebeskind, David; Traylor, Matthew; Tan, Rhea; Danesh, John; Rutten-Jacobs, Loes; Donatti, Amanda; Avelar, Wagner; Broderick, Joseph; Woo, Daniel; Sudlow, Cathie; Rannikmae, Kristiina; McDonough, Caitrin Wheeler; van Agtmael, Tom; Walters, Matthew; Söderholm, Martin; Lorentzen, Erik; Olsson, Sandra; Stanne, Tara; Olsson, Martina; Akinyemi, Rufus; Cotlatciuc, Ioana; McArdle, Patrick; Dave, Tushar; Kittner, Steven; Attia, John; Faber, James E; Millwood, Iona; Márquez, Elsa Valdés; Mancuso, Michelangelo; Vibo, Riina; Korv, Janika; Maguire, Jane; Fornage, Myriam; Majersik, Jennifer; DeHavenon, Adam; Alexander, Matthew; Sale, Michele; Southerland, Andrew; Owens, Debra; Psaty, Bruce; Longstreth, W. T.; Wolfe, Stacey Quintero; Langefeld, Carl; Cruchaga, Carlos; Konrad, Jan; Sheth, Kevin; Falcone, Guido; Donahue, Kathleen; Simpkins, Alexis N; Liang Byorn, Tan Wei; Chan, Bernard; Clatworthy, Phil; Florez, Jose; Harshfield, Eric; Hozawa, Atsushi; Hsu, Chung; Hu, Chaur-Jong; Ibanez, Laure; Ihara, Masafumi; Lange, Marcos; Lee, Soo Ji; Lee, I-Hui; Musolino, Patricia; Nakatomi, Hirofumi; Park, Kwang-Yeol; Rich, Stephen S; Riley, Chris; Sung, Joohon; Suzuki, Hideaki; Vo, Katie; Washida, Kazuo; Ibenez, Laura Garcia; Slowik, Agnieszka; Hofman, Albert; Algra, Ale; Reiner, Alex P; Doney, Alexander S F; Gschwendtner, Andreas; Ilinca, Andreea; Giese, Anne-Katrin; Lindgren, Arne; Vicente, Astrid M; Norrving, Bo; Nordestgaard, Børge G; Mitchell, Braxton D; Worrall, Bradford B; Psaty, Bruce M; Carty, Cara L; Sudlow, Cathie; Anderson, Christopher D; Levi, Christopher; Satizabal, Claudia L; Palmer, Colin N A; Gamble, Dale M; Woo, Daniel; Saleheen, Danish; Ringelstein, E Bernd; Valdimarsson, Einar; Holliday, Elizabeth; Davies, Gail; Chauhan, Ganesh; Pasterkamp, Gerard; Boncoraglio, Giorgio; Kuhlenbäumer, Gregor; Thorleifsson, Gudmar; Falcone, Guido J; Pare, Guillame; Schmidt, Helena; Delavaran, Hossein; Markus, Hugh S; Aparicio, Hugo J; Deary, Ian; Cotlarciuc, Ioana; Fernandez-Cadenas, Israel; Meschia, James; Hopewell, Jemma C; Liu, Jingmin; Montaner, Joan; Pera, Joanna; Cole, John; Attia, John R; Rosand, Jonathan; Ferro, Jose M; Bis, Joshua; Furie, Karen; Stefansson, Kari; Berger, Klaus; Kostulas, Konstantinos; Rannikmae, Kristina; Ikram, M Arfan; Benn, Marianne; Dichgans, Martin; Farrall, Martin; Pandolfo, Massimo; Traylor, Matthew; Walters, Matthew; Sale, Michele; Nalls, Mike; Fornage, Myriam; van Zuydam, Natalie R; Sharma, Pankaj; Abrantes, Patricia; de Bakker, Paul IW; Higgins, Peter; Lichtner, Peter; Rothwell, Peter M; Amouyel, Philippe; Yang, Qiong; Malik, Rainer; Schmidt, Reinhold; Clarke, Robert; Lemmens, Robin; van der Laan, Sander W; Pulit, Sara L; Abboud, Sherine; Oliveira, Sofia A; Gretarsdottir, Solveig; Debette, Stephanie; Williams, Stephen R; Bevan, Steve; Kittner, Steven J; Seshadri, Sudha; Mosley, Thomas; Battey, Thomas WK; Tatlisumak, Turgut; Thorsteinsdottir, Unnur; Thijs, Vincent NS; Longstreth, W T; Zhao, Wei; Chen, Wei-Min; Cheng, Yu-Ching; Albert, Marilyn S.; Albin, Roger L.; Apostolova, Liana G.; Arnold, Steven E.; Asthana, Sanjay; Atwood, Craig S.; Baldwin, Clinton T.; Barmada, M. Michael; Barnes, Lisa L.; Barral, Sandra; Beach, Thomas G.; Becker, James T.; Beecham, Gary W.; Beekly, Duane; Bennett, David A.; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boeve, Bradley F.; Boxer, Adam; Burke, James R.; Burns, Jeffrey M.; Buxbaum, Joseph D.; Byrd, Goldie S.; Cai, Guiqing; Cairns, Nigel J.; Cantwell, Laura B.; Cao, Chuanhai; Carlsson, Cynthia M.; Carney, Regina M.; Carrasquillo, Minerva M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Cribbs, David H.; Crocco, Elizabeth A.; Cruchaga, Carlos; De Jager, Philip L.; DeCarli, Charles; Demirci, F. Yesim; Dick, Malcolm; Dickson, Dennis W.; Duara, Ranjan; Ertekin-Taner, Nilufer; Evans, Denis A.; Faber, Kelley M.; Fallin, M. Daniele; Fallon, Kenneth B.; Fardo, David W.; Farlow, Martin R.; Farrer, Lindsay A.; Ferris, Steven; Foroud, Tatiana M.; Frosch, Matthew P.; Galasko, Douglas R.; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John R.; Go, Rodney C.P.; Goate, Alison M.; Graff-Radford, Neill R.; Green, Robert C.; Griffith, Patrick; Growdon, John H.; Haines, Jonathan L.; Hakonarson, Hakon; Hamilton, Ronald L.; Hamilton-Nelson, Kara L.; Haroutunian, Vahram; Harrell, Lindy E.; Honig, Lawrence S.; Huebinger, Ryan M.; Hulette, Christine M.; Hyman, Bradley T.; Jicha, Gregory A.; Jin, Lee-Way; Jun, Gyungah; Kamboh, M. 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Kamran; Adams, Hieab H.; Beecham, Ashley H.; Rajan, Kumar B.; Lopez, Lorna M.; Barral, Sandra; van Buchem, Mark A.; van der Grond, Jeroen; Smith, Albert V.; Hegenscheid, Katrin; Aggarwal, Neelum T.; de Andrade, Mariza; Atkinson, Elizabeth J.; Beekman, Marian; Beiser, Alexa S.; Blanton, Susan H.; Boerwinkle, Eric; Brickman, Adam M.; Bryan, R. Nick; Chauhan, Ganesh; Chen, Christopher P.L.H.; Chouraki, Vincent; de Craen, Anton J.M.; Crivello, Fabrice; Deary, Ian J.; Deelen, Joris; De Jager, Philip L.; Dufouil, Carole; Elkind, Mitchell S.V.; Evans, Denis A.; Freudenberger, Paul; Gottesman, Rebecca F.; Guðnason, Vilmundur; Habes, Mohamad; Heckbert, Susan R.; Heiss, Gerardo; Hilal, Saima; Hofer, Edith; Hofman, Albert; Ibrahim-Verbaas, Carla A.; Knopman, David S.; Lewis, Cora E.; Liao, Jiemin; Liewald, David C.M.; Luciano, Michelle; van der Lugt, Aad; Martinez, Oliver O.; Mayeux, Richard; Mazoyer, Bernard; Nalls, Mike; Nauck, Matthias; Niessen, Wiro J.; Oostra, Ben A.; Psaty, Bruce M.; Rice, Kenneth M.; Rotter, Jerome I.; von Sarnowski, Bettina; Schmidt, Helena; Schreiner, Pamela J.; Schuur, Maaike; Sidney, Stephen S.; Sigurdsson, Sigurdur; Slagboom, P. Eline; Stott, David J.M.; van Swieten, John C.; Teumer, Alexander; Töglhofer, Anna Maria; Traylor, Matthew; Trompet, Stella; Turner, Stephen T.; Tzourio, Christophe; Uh, Hae-Won; Uitterlinden, André G.; Vernooij, Meike W.; Wang, Jing J.; Wong, Tien Y.; Wardlaw, Joanna M.; Windham, B. Gwen; Wittfeld, Katharina; Wolf, Christiane; Wright, Clinton B.; Yang, Qiong; Zhao, Wei; Zijdenbos, Alex; Jukema, J. Wouter; Sacco, Ralph L.; Kardia, Sharon L.R.; Amouyel, Philippe; Mosley, Thomas H.; Longstreth, W. T.; DeCarli, Charles C.; van Duijn, Cornelia M.; Schmidt, Reinhold; Launer, Lenore J.; Grabe, Hans J.; Seshadri, Sudha S.; Ikram, M. Arfan; Fornage, Myriam; Bis, Joshua C.; Kavousi, Maryam; Franceschini, Nora; Isaacs, Aaron; Abecasis, Gonçalo R; Schminke, Ulf; Post, Wendy; Smith, Albert V.; Cupples, L. Adrienne; Markus, Hugh S; Schmidt, Reinhold; Huffman, Jennifer E.; Lehtimäki, Terho; Baumert, Jens; Münzel, Thomas; Heckbert, Susan R.; Dehghan, Abbas; North, Kari; Oostra, Ben; Bevan, Steve; Stoegerer, Eva-Maria; Hayward, Caroline; Raitakari, Olli; Meisinger, Christa; Schillert, Arne; Sanna, Serena; Völzke, Henry; Cheng, Yu-Ching; Thorsson, Bolli; Fox, Caroline S.; Rice, Kenneth; Rivadeneira, Fernando; Nambi, Vijay; Halperin, Eran; Petrovic, Katja E.; Peltonen, Leena; Wichmann, H. Erich; Schnabel, Renate B.; Dörr, Marcus; Parsa, Afshin; Aspelund, Thor; Demissie, Serkalem; Kathiresan, Sekar; Reilly, Muredach P.; Taylor, Kent; Uitterlinden, Andre; Couper, David J.; Sitzer, Matthias; Kähönen, Mika; Illig, Thomas; Wild, Philipp S.; Orru, Marco; Lüdemann, Jan; Shuldiner, Alan R.; Eiriksdottir, Gudny; White, Charles C.; Rotter, Jerome I.; Hofman, Albert; Seissler, Jochen; Zeller, Tanja; Usala, Gianluca; Ernst, Florian; Launer, Lenore J.; D'Agostino, Ralph B.; O'Leary, Daniel H.; Ballantyne, Christie; Thiery, Joachim; Ziegler, Andreas; Lakatta, Edward G.; Chilukoti, Ravi Kumar; Harris, Tamara B.; Wolf, Philip A.; Psaty, Bruce M.; Polak, Joseph F; Li, Xia; Rathmann, Wolfgang; Uda, Manuela; Boerwinkle, Eric; Klopp, Norman; Schmidt, Helena; Wilson, James F; Viikari, Jorma; Koenig, Wolfgang; Blankenberg, Stefan; Newman, Anne B.; Witteman, Jacqueline; Heiss, Gerardo; van Duijn, Cornelia; Scuteri, Angelo; Homuth, Georg; Mitchell, Braxton D.; Gudnason, Vilmundur; O'Donnell, Christopher J.;
• Is Part Of: Neurology. Volume 92:Number 5(2019)
• Publication Date: 2019-01-29
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000006851
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20, 949) from 5 ethnicities (3, 726 with BI, 2, 021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6, 862; 1, 483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 ; and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 ; p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 ; p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 ; p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 ; p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 ; p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 ; p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ⩽ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20, 000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.