RT Journal Article
SR Electronic
T1 Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
JF Neurology
JO Neurology
FD Lippincott Williams & Wilkins
SP e486
OP e503
DO 10.1212/WNL.0000000000006851
VO 92
IS 5
A1 Chauhan, Ganesh
A1 Adams, Hieab H.H.
A1 Satizabal, Claudia L.
A1 Bis, Joshua C.
A1 Teumer, Alexander
A1 Sargurupremraj, Muralidharan
A1 Hofer, Edith
A1 Trompet, Stella
A1 Hilal, Saima
A1 Smith, Albert Vernon
A1 Jian, Xueqiu
A1 Malik, Rainer
A1 Traylor, Matthew
A1 Pulit, Sara L.
A1 Amouyel, Philippe
A1 Mazoyer, Bernard
A1 Zhu, Yi-Cheng
A1 Kaffashian, Sara
A1 Schilling, Sabrina
A1 Beecham, Gary W.
A1 Montine, Thomas J.
A1 Schellenberg, Gerard D.
A1 Kjartansson, Olafur
A1 Guðnason, Vilmundur
A1 Knopman, David S.
A1 Griswold, Michael E.
A1 Windham, B. Gwen
A1 Gottesman, Rebecca F.
A1 Mosley, Thomas H.
A1 Schmidt, Reinhold
A1 Saba, Yasaman
A1 Schmidt, Helena
A1 Takeuchi, Fumihiko
A1 Yamaguchi, Shuhei
A1 Nabika, Toru
A1 Kato, Norihiro
A1 Rajan, Kumar B.
A1 Aggarwal, Neelum T.
A1 De Jager, Philip L.
A1 Evans, Denis A.
A1 Psaty, Bruce M.
A1 Rotter, Jerome I.
A1 Rice, Kenneth
A1 Lopez, Oscar L.
A1 Liao, Jiemin
A1 Chen, Christopher
A1 Cheng, Ching-Yu
A1 Wong, Tien Y.
A1 Ikram, Mohammad K.
A1 van der Lee, Sven J.
A1 Amin, Najaf
A1 Chouraki, Vincent
A1 DeStefano, Anita L.
A1 Aparicio, Hugo J.
A1 Romero, Jose R.
A1 Maillard, Pauline
A1 DeCarli, Charles
A1 Wardlaw, Joanna M.
A1 Hernández, Maria del C. Valdés
A1 Luciano, Michelle
A1 Liewald, David
A1 Deary, Ian J.
A1 Starr, John M.
A1 Bastin, Mark E.
A1 Muñoz Maniega, Susana
A1 Slagboom, P. Eline
A1 Beekman, Marian
A1 Deelen, Joris
A1 Uh, Hae-Won
A1 Lemmens, Robin
A1 Brodaty, Henry
A1 Wright, Margaret J.
A1 Ames, David
A1 Boncoraglio, Giorgio B.
A1 Hopewell, Jemma C.
A1 Beecham, Ashley H.
A1 Blanton, Susan H.
A1 Wright, Clinton B.
A1 Sacco, Ralph L.
A1 Wen, Wei
A1 Thalamuthu, Anbupalam
A1 Armstrong, Nicola J.
A1 Chong, Elizabeth
A1 Schofield, Peter R.
A1 Kwok, John B.
A1 van der Grond, Jeroen
A1 Stott, David J.
A1 Ford, Ian
A1 Jukema, J. Wouter
A1 Vernooij, Meike W.
A1 Hofman, Albert
A1 Uitterlinden, André G.
A1 van der Lugt, Aad
A1 Wittfeld, Katharina
A1 Grabe, Hans J.
A1 Hosten, Norbert
A1 von Sarnowski, Bettina
A1 Völker, Uwe
A1 Levi, Christopher
A1 Jimenez-Conde, Jordi
A1 Sharma, Pankaj
A1 Sudlow, Cathie L.M.
A1 Rosand, Jonathan
A1 Woo, Daniel
A1 Cole, John W.
A1 Meschia, James F.
A1 Slowik, Agnieszka
A1 Thijs, Vincent
A1 Lindgren, Arne
A1 Melander, Olle
A1 Grewal, Raji P.
A1 Rundek, Tatjana
A1 Rexrode, Kathy
A1 Rothwell, Peter M.
A1 Arnett, Donna K.
A1 Jern, Christina
A1 Johnson, Julie A.
A1 Benavente, Oscar R.
A1 Wasssertheil-Smoller, Sylvia
A1 Lee, Jin-Moo
A1 Wong, Quenna
A1 Mitchell, Braxton D.
A1 Rich, Stephen S.
A1 McArdle, Patrick F.
A1 Geerlings, Mirjam I.
A1 van der Graaf, Yolanda
A1 de Bakker, Paul I.W.
A1 Asselbergs, Folkert W.
A1 Srikanth, Velandai
A1 Thomson, Russell
A1 McWhirter, Rebekah
A1 Moran, Chris
A1 Callisaya, Michele
A1 Phan, Thanh
A1 Rutten-Jacobs, Loes C.A.
A1 Bevan, Steve
A1 Tzourio, Christophe
A1 Mather, Karen A.
A1 Sachdev, Perminder S.
A1 van Duijn, Cornelia M.
A1 Worrall, Bradford B.
A1 Dichgans, Martin
A1 Kittner, Steven J.
A1 Markus, Hugh S.
A1 Ikram, Mohammad A.
A1 Fornage, Myriam
A1 Launer, Lenore J.
A1 Seshadri, Sudha
A1 Longstreth, W.T.
A1 Debette, Stéphanie
YR 2019
UL http://n.neurology.org/content/92/5/e486.abstract
AB 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.1000G=1000 Genomes reference panel; BI=brain infarcts; BMI=body mass index; BP=blood pressure; DBP=diastolic blood pressure; FLAIR=fluid-attenuated inversion recovery; GRS=genetic risk scores; GWAS=genome-wide association studies; HDL=high-density lipoprotein; IS=ischemic stroke; IS-SVD=small vessel disease subtype of ischemic stroke; IVW=inverse-variance weighting; L10BF=Log10 of Bayesian factor; LD=linkage disequilibrium; LDL=low-density lipoprotein; MAP=mean arterial pressure; PP=pulse pressure; SNP=single nucleotide polymorphism; SBP=systolic blood pressure; SSBI=small subcortical brain infarcts; SVD=small vessel disease; WMH=white matter hyperintensities