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

Authors:
Ganesh Chauhan Hieab H H Adams Claudia L Satizabal Joshua C Bis Alexander Teumer Muralidharan Sargurupremraj Edith Hofer Stella Trompet Saima Hilal Albert Vernon Smith Xueqiu Jian Rainer Malik Matthew Traylor Sara L Pulit Philippe Amouyel Bernard Mazoyer Yi-Cheng Zhu Sara Kaffashian Sabrina Schilling Gary W Beecham Thomas J Montine Gerard D Schellenberg Olafur Kjartansson Vilmundur Guðnason David S Knopman Michael E Griswold B Gwen Windham Rebecca F Gottesman Thomas H Mosley Reinhold Schmidt Yasaman Saba Helena Schmidt Fumihiko Takeuchi Shuhei Yamaguchi Toru Nabika Norihiro Kato Kumar B Rajan Neelum T Aggarwal Philip L De Jager Denis A Evans Bruce M Psaty Jerome I Rotter Kenneth Rice Oscar L Lopez Jiemin Liao Christopher Chen Ching-Yu Cheng Tien Y Wong Mohammad K Ikram Sven J van der Lee Najaf Amin Vincent Chouraki Anita L DeStefano Hugo J Aparicio Jose R Romero Pauline Maillard Charles DeCarli Joanna M Wardlaw Maria Del C Valdés Hernández Michelle Luciano David Liewald Ian J Deary John M Starr Mark E Bastin Susana Muñoz Maniega P Eline Slagboom Marian Beekman Joris Deelen Hae-Won Uh Robin Lemmens Henry Brodaty Margaret J Wright David Ames Giorgio B Boncoraglio Jemma C Hopewell Ashley H Beecham Susan H Blanton Clinton B Wright Ralph L Sacco Wei Wen Anbupalam Thalamuthu Nicola J Armstrong Elizabeth Chong Peter R Schofield John B Kwok Jeroen van der Grond David J Stott Ian Ford J Wouter Jukema Meike W Vernooij Albert Hofman André G Uitterlinden Aad van der Lugt Katharina Wittfeld Hans J Grabe Norbert Hosten Bettina von Sarnowski Uwe Völker Christopher Levi Jordi Jimenez-Conde Pankaj Sharma Cathie L M Sudlow Jonathan Rosand Daniel Woo John W Cole James F Meschia Agnieszka Slowik Vincent Thijs Arne Lindgren Olle Melander Raji P Grewal Tatjana Rundek Kathy Rexrode Peter M Rothwell Donna K Arnett Christina Jern Julie A Johnson Oscar R Benavente Sylvia Wasssertheil-Smoller Jin-Moo Lee Quenna Wong Braxton D Mitchell Stephen S Rich Patrick F McArdle Mirjam I Geerlings Yolanda van der Graaf Paul I W de Bakker Folkert W Asselbergs Velandai Srikanth Russell Thomson Rebekah McWhirter Chris Moran Michele Callisaya Thanh Phan Loes C A Rutten-Jacobs Steve Bevan Christophe Tzourio Karen A Mather Perminder S Sachdev Cornelia M van Duijn Bradford B Worrall Martin Dichgans Steven J Kittner Hugh S Markus Mohammad A Ikram Myriam Fornage Lenore J Launer Sudha Seshadri W T Longstreth Stéphanie Debette

Neurology 2019 Jan 16. Epub 2019 Jan 16.

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, = 1.77 × 10; and LINC00539/ZDHHC20, = 5.82 × 10. 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 ( value for BI, = 9.38 × 10; = 5.23 × 10 for hypertension), smoking ( = 4.4 × 10; = 1.2 × 10), diabetes ( = 1.7 × 10; = 2.8 × 10), previous cardiovascular disease ( = 1.0 × 10; = 2.3 × 10), stroke ( = 3.9 × 10; = 3.2 × 10), and MRI-defined white matter hyperintensity burden ( = 1.43 × 10; = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( ≤ 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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Source
http://dx.doi.org/10.1212/WNL.0000000000006851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905PMC
January 2019
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