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Neurology. 2019 Jan 16. pii: 10.1212/WNL.0000000000006851. doi: 10.1212/WNL.0000000000006851. [Epub ahead of print]

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Chauhan G, Adams HHH, Satizabal CL, Bis JC, Teumer A, Sargurupremraj M, Hofer E, Trompet S, Hilal S, Smith AV, Jian X, Malik R, Traylor M, Pulit SL, Amouyel P, Mazoyer B, Zhu YC, Kaffashian S, Schilling S, Beecham GW, Montine TJ, Schellenberg GD, Kjartansson O, Guðnason V, Knopman DS, Griswold ME, Windham BG, Gottesman RF, Mosley TH, Schmidt R, Saba Y, Schmidt H, Takeuchi F, Yamaguchi S, Nabika T, Kato N, Rajan KB, Aggarwal NT, De Jager PL, Evans DA, Psaty BM, Rotter JI, Rice K, Lopez OL, Liao J, Chen C, Cheng CY, Wong TY, Ikram MK, van der Lee SJ, Amin N, Chouraki V, DeStefano AL, Aparicio HJ, Romero JR, Maillard P, DeCarli C, Wardlaw JM, Hernández MDCV, Luciano M, Liewald D, Deary IJ, Starr JM, Bastin ME, Muñoz Maniega S, Slagboom PE, Beekman M, Deelen J, Uh HW, Lemmens R, Brodaty H, Wright MJ, Ames D, Boncoraglio GB, Hopewell JC, Beecham AH, Blanton SH, Wright CB, Sacco RL, Wen W, Thalamuthu A, Armstrong NJ, Chong E, Schofield PR, Kwok JB, van der Grond J, Stott DJ, Ford I, Jukema JW, Vernooij MW, Hofman A, Uitterlinden AG, van der Lugt A, Wittfeld K, Grabe HJ, Hosten N, von Sarnowski B, Völker U, Levi C, Jimenez-Conde J, Sharma P, Sudlow CLM, Rosand J, Woo D, Cole JW, Meschia JF, Slowik A, Thijs V, Lindgren A, Melander O, Grewal RP, Rundek T, Rexrode K, Rothwell PM, Arnett DK, Jern C, Johnson JA, Benavente OR, Wasssertheil-Smoller S, Lee JM, Wong Q, Mitchell BD, Rich SS, McArdle PF, Geerlings MI, van der Graaf Y, de Bakker PIW, Asselbergs FW, Srikanth V, Thomson R, McWhirter R, Moran C, Callisaya M, Phan T, Rutten-Jacobs LCA, Bevan S, Tzourio C, Mather KA, Sachdev PS, van Duijn CM, Worrall BB, Dichgans M, Kittner SJ, Markus HS, Ikram MA, Fornage M, Launer LJ, Seshadri S, Longstreth WT Jr, Debette S; Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

Collaborators (845)

Almgren P, Anderson CD, Arnett DK, Attia J, Ay H, Benavente OR, Bevan S, Brown RD, Bustamante M, Cheng YC, Cole JW, Cotlarciuc I, Cruchaga C, de Bakker PI, Delavaran H, Dichgans M, Engström G, Fornage M, Grewal RP, Heitsch L, Holliday E, Ibanez L, Ilinca A, Irvin MR, Jackson RD, Jern C, Jimenez-Conde J, Johnson JA, Jood K, Kissela BM, Kittner SJ, Kleindorfer DO, Labovitz D, Laurie CC, Lee JM, Lemmens R, Levi C, Li L, Lindgren AG, Maguire J, Markus HS, McArdle PF, Melander O, Meschia JF, Mitchell BD, Müller-Nurasyid M, Norrving B, Peddareddygari LR, Pera J, Pulit SL, Rexrode K, Ribasés M, Roquer J, Rost NS, Rothwell PM, Rundek T, Sacco RL, Schmidt R, Sharma P, Slowik A, Soriano-Tárraga C, Stanne T, Stauch K, Stine OC, Sudlow CL, Thijs VNS, Wasssertheil-Smoller S, Weir D, Williams SR, Wong Q, Woo D, Worrall BB, Xu H, Seshadri S, Hyacinth HI, Marini S, Nyquist P, Lewis C, Hansen B, Norrving B, Rosand J, Biffi A, Kourkoulis C, Anderson C, Giese AK, Sacco R, Sharma P, Chung JW, Kim GM, Lubitz S, Bourcier R, Howson J, Granata A, Drazyk A, Markus H, Wardlaw J, Mitchell B, Cole J, Hopewell J, Walters R, Turnbull I, Worrall B, Bis J, Reiner A, Dhar R, Heitsch L, Lee JM, Prasad K, Sarnowski C, Aparicio HJ, Yang Q, Chasman D, Rexrode K, Phuah CL, Liu G, Elkind M, Lange L, Rost N, James M, Stewart J, Vojinovic D, Thijs V, Parati E, Boncoraglio G, Zand R, Bijlenga P, Selim M, Grond-Ginsbach C, Strbian D, Tomppo L, Sallinen H, Pfeiffer D, Torres N, Barboza M, Laarman M, Carriero R, Holliday E, Jimenez-Conde J, Soriano C, Gill D, Debette S, Mishra A, Wu JY, Ko TM, Bione S, Jood K, Tatlisumak T, Holmegaard L, Yue S, Bersano A, Pera J, Slowik A, Levi C, Schlicht K, Lemmens R, Ninomiya T, Oberstein SL, Lee TH, Malik R, Dichgans M, Lindgren A, Wasselius J, Drake M, Melander O, Stenman M, Ilinca A, Crawford K, Lena U, Mateen F, Ay H, Wu O, Schirmer M, Cramer S, Golland P, Brown R, Meschia J, Ross OA, Pare G, Chong M, Rundek T, Gwinn K, Chen C, Koenig J, Giralt E, Saleheen D, de Leeuw FE, Klijn K, Kamatani Y, Kubo M, Okada Y, Pedersen A, Olsson M, Martín JJ, Xu H, Tan EK, Frid P, Lee C, Tregouet D, Leung T, Choy R, Jern C, Loo KW, Rinkel G, Franca P, Cendes I, Carrera C, Fernandez-Cadenas I, Montaner J, Kim H, Owolabi M, Sofat R, Bakker M, Ruigrok Y, Hauer A, Pulit SL, van der Laan SW, Irvin R, Sargurupremraj M, Pezzini A, Abd-Allah F, Liebeskind D, Traylor M, Tan R, Danesh J, Rutten-Jacobs L, Donatti A, Avelar W, Broderick J, Woo D, Sudlow C, Rannikmae K, McDonough CW, van Agtmael T, Walters M, Söderholm M, Lorentzen E, Olsson S, Stanne T, Olsson M, Akinyemi R, Cotlatciuc I, McArdle P, Dave T, Kittner S, Attia J, Faber JE, Millwood I, Márquez EV, Mancuso M, Vibo R, Korv J, Maguire J, Fornage M, Majersik J, DeHavenon A, Alexander M, Sale M, Southerland A, Owens D, Psaty B, Longstreth WT Jr, Wolfe SQ, Langefeld C, Cruchaga C, Konrad J, Sheth K, Falcone G, Donahue K, Simpkins AN, Liang Byorn TW, Chan B, Clatworthy P, Florez J, Harshfield E, Hozawa A, Hsu C, Hu CJ, Ibanez L, Ihara M, Lange M, Lee SJ, Lee IH, Musolino P, Nakatomi H, Park KY, Rich SS, Riley C, Sung J, Suzuki H, Vo K, Washida K, Ibenez LG, Slowik A, Hofman A, Algra A, Reiner AP, Doney ASF, Gschwendtner A, Ilinca A, Giese AK, Lindgren A, Vicente AM, Norrving B, Nordestgaard BG, Mitchell BD, Worrall BB, Psaty BM, Carty CL, Sudlow C, Anderson CD, Levi C, Satizabal CL, Palmer CNA, Gamble DM, Woo D, Saleheen D, Ringelstein EB, Valdimarsson E, Holliday E, Davies G, Chauhan G, Pasterkamp G, Boncoraglio G, Kuhlenbäumer G, Thorleifsson G, Falcone GJ, Pare G, Schmidt H, Delavaran H, Markus HS, Aparicio HJ, Deary I, Cotlarciuc I, Fernandez-Cadenas I, Meschia J, Hopewell JC, Liu J, Montaner J, Pera J, Cole J, Attia JR, Rosand J, Ferro JM, Bis J, Furie K, Stefansson K, Berger K, Kostulas K, Rannikmae K, Ikram MA, Benn M, Dichgans M, Farrall M, Pandolfo M, Traylor M, Walters M, Sale M, Nalls M, Fornage M, van Zuydam NR, Sharma P, Abrantes P, de Bakker PI, Higgins P, Lichtner P, Rothwell PM, Amouyel P, Yang Q, Malik R, Schmidt R, Clarke R, Lemmens R, van der Laan SW, Pulit SL, Abboud S, Oliveira SA, Gretarsdottir S, Debette S, Williams SR, Bevan S, Kittner SJ, Seshadri S, Mosley T, Battey TW, Tatlisumak T, Thorsteinsdottir U, Thijs VN, Longstreth WT, Zhao W, Chen WM, Cheng YC, Albert MS, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barmada MM, Barnes LL, Barral S, Beach TG, Becker JT, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Boxer A, Burke JR, Burns JM, Buxbaum JD, Byrd GS, Cai G, Cairns NJ, Cantwell LB, Cao C, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Cribbs DH, Crocco EA, Cruchaga C, De Jager PL, DeCarli C, Demirci FY, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Evans DA, Faber KM, Fallin MD, Fallon KB, Fardo DW, Farlow MR, Farrer LA, Ferris S, Foroud TM, Frosch MP, Galasko DR, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Go RCP, Goate AM, Graff-Radford NR, Green RC, Griffith P, Growdon JH, Haines JL, Hakonarson H, Hamilton RL, Hamilton-Nelson KL, Haroutunian V, Harrell LE, Honig LS, Huebinger RM, Hulette CM, Hyman BT, Jicha GA, Jin LW, Jun G, Kamboh MI, Karydas A, Kauwe JSK, Kaye JA, Kim R, Kowall NW, Kramer JH, Kukull WA, Kunkle BW, LaFerla FM, Lah JJ, Lang-Walker R, Larson EB, Leverenz JB, Levey AI, Li G, Lieberman AP, Logue MW, Lopez OL, Lunetta KL, Lyketsos CG, Mack WJ, Manly JJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, Mayeux R, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Murrell JR, Naj AC, Obisesan TO, Olichney JM, Pankratz VS, Parisi JE, Partch A, Paulson HL, Pericak-Vance MA, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raj T, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sager MA, Sano M, Saykin AJ, Schellenberg GD, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, Valladares O, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Wang LS, Weintraub S, Welsh-Bohmer KA, Williamson J, Wingo TS, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L, Chauhan G, Chu AY, Fornage M, Bis JC, Havulinna AS, Sargurupremraj M, Smith AV, Adams HHH, Choi SH, Trompet S, Garcia ME, Manichaikul A, Teumer A, Gustafsson S, Bartz TM, Bellenguez C, Vidal JS, Jian X, Kjartansson O, Wiggins KL, Satizabal CL, Xue F, Ripatti S, Liu Y, Deelen J, Hoed MD, Heckbert SR, Rice K, Smith NL, Wong Q, Aparicio HJ, Buring JE, Ridker PM, Berr C, Dartigues JF, Hamsten A, Magnusson PK, Pedersen NL, Lannfelt L, Lind L, Lindgren CM, Morris AP, Hofman A, Koudstaal PJ, Portegies ML, Uitterlinden AG, de Craen AJ, Ford I, Jukema JW, Stott DJ, Allen NB, Sale MM, Johnson AD, Bennett DA, De Jager PL, White CC, Grabe HJ, Paulista Markus MR, Lopez OL, Rotter JI, Nalls MA, Gottesman RF, Griswold ME, Knopman DS, Windham BG, Beiser A, Vartiainen E, French CR, Kurth T, Psaty BM, Harris TB, Rich SS, deStefano AL, Schmidt CO, Salomaa V, Mosley TH, Ingelsson E, van Duijn CM, Tzourio C, Launer LJ, Ikram MA, Chasman DI, Longstreth WT Jr, Seshadri S, Debette S, Verhaaren BFJ, Debette S, Bis JC, Smith JA, Ikram MK, Adams HH, Beecham AH, Rajan KB, Lopez LM, Barral S, van Buchem MA, van der Grond J, Smith AV, Hegenscheid K, Aggarwal NT, de Andrade M, Atkinson EJ, Beekman M, Beiser AS, Blanton SH, Boerwinkle E, Brickman AM, Bryan RN, Chauhan G, Chen CPLH, Chouraki V, de Craen AJM, Crivello F, Deary IJ, Deelen J, De Jager PL, Dufouil C, Elkind MSV, Evans DA, Freudenberger P, Gottesman RF, Guðnason V, Habes M, Heckbert SR, Heiss G, Hilal S, Hofer E, Hofman A, Ibrahim-Verbaas CA, Knopman DS, Lewis CE, Liao J, Liewald DCM, Luciano M, van der Lugt A, Martinez OO, Mayeux R, Mazoyer B, Nalls M, Nauck M, Niessen WJ, Oostra BA, Psaty BM, Rice KM, Rotter JI, von Sarnowski B, Schmidt H, Schreiner PJ, Schuur M, Sidney SS, Sigurdsson S, Slagboom PE, Stott DJM, van Swieten JC, Teumer A, Töglhofer AM, Traylor M, Trompet S, Turner ST, Tzourio C, Uh HW, Uitterlinden AG, Vernooij MW, Wang JJ, Wong TY, Wardlaw JM, Windham BG, Wittfeld K, Wolf C, Wright CB, Yang Q, Zhao W, Zijdenbos A, Jukema JW, Sacco RL, Kardia SLR, Amouyel P, Mosley TH, Longstreth WT Jr, DeCarli CC, van Duijn CM, Schmidt R, Launer LJ, Grabe HJ, Seshadri SS, Ikram MA, Fornage M, Bis JC, Kavousi M, Franceschini N, Isaacs A, Abecasis GR, Schminke U, Post W, Smith AV, Cupples LA, Markus HS, Schmidt R, Huffman JE, Lehtimäki T, Baumert J, Münzel T, Heckbert SR, Dehghan A, North K, Oostra B, Bevan S, Stoegerer EM, Hayward C, Raitakari O, Meisinger C, Schillert A, Sanna S, Völzke H, Cheng YC, Thorsson B, Fox CS, Rice K, Rivadeneira F, Nambi V, Halperin E, Petrovic KE, Peltonen L, Wichmann HE, Schnabel RB, Dörr M, Parsa A, Aspelund T, Demissie S, Kathiresan S, Reilly MP, Taylor K, Uitterlinden A, Couper DJ, Sitzer M, Kähönen M, Illig T, Wild PS, Orru M, Lüdemann J, Shuldiner AR, Eiriksdottir G, White CC, Rotter JI, Hofman A, Seissler J, Zeller T, Usala G, Ernst F, Launer LJ, D'Agostino RB Sr, O'Leary DH, Ballantyne C, Thiery J, Ziegler A, Lakatta EG, Chilukoti RK, Harris TB, Wolf PA, Psaty BM, Polak JF, Li X, Rathmann W, Uda M, Boerwinkle E, Klopp N, Schmidt H, Wilson JF, Viikari J, Koenig W, Blankenberg S, Newman AB, Witteman J, Heiss G, van Duijn C, Scuteri A, Homuth G, Mitchell BD, Gudnason V, O'Donnell CJ.

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.

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