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

Ganesh Chauhan 1 Hieab Adams Claudia Satizabal Joshua Bis Alexander Teumer Muralidharan Sargurupremraj Edith Hofer Stella Trompet Saima Hilal Albert Smith Xueqiu Jian Rainer Malik Matthew Traylor Sara Pulit Philippe Amouyel Bernard Mazoyer Yi-Cheng Zhu Sara Kaffashian Sabrina Schilling Gary Beecham Thomas Montine Gerard Schellenberg Olafur Kjartansson Vilmundur Guðnason David Knopman Michael Griswold B Windham Rebecca Gottesman Thomas Mosley Reinhold Schmidt Yasaman Saba Helena Schmidt Fumihiko Takeuchi Shuhei Yamaguchi Toru Nabika Norihiro Kato Kumar Rajan Neelum Aggarwal Philip de Jager Denis Evans Bruce Psaty Jerome Rotter Kenneth Rice Oscar Lopez Jiemin Liao Christopher Ma Ching-Yu Chen Tien Cheng Mohammad Wong Sven Ikram Najaf van der Lee Vincent Amin Anita Chouraki Hugo Destefano Jose Aparicio Pauline Romero Charles Maillard Joanna Decarli Maria Wardlaw Michelle Valdés Hernández David Luciano Ian Liewald John Deary Mark Starr Susana Bastin Marian Slagboom Joris Beekman Hae-Won Deelen Robin Uh Henry Lemmens Margaret Brodaty David Wright Giorgio Ames Jemma Boncoraglio Ashley Hopewell Susan Beecham Clinton Blanton Ralph Wright Wei Sacco Anbupalam Wen Nicola Thalamuthu Elizabeth Armstrong Peter Chong John Schofield Jeroen Kwok David van der Grond Ian Stott J Ford Meike Jukema Albert Vernooij André Hofman Aad Uitterlinden Katharina van der Lugt Hans Wittfeld Norbert Grabe Bettina Hosten Uwe von Sarnowski Christopher Völker Jordi Levi Pankaj Jimenez-Conde Cathie Sudlow Jonathan Rosand Daniel Woo John Cole James Meschia Agnieszka Slowik Vincent Thijs Arne Lindgren Olle Melander 2 Raji Grewal Tatjana Rundek Kathy Rexrode Peter Rothwell Donna Arnett Christina Jern Julie Johnson Oscar Benavente Sylvia Wasssertheil-Smoller Jin-Moo Lee Quenna Wong Braxton Mitchell Stephen Rich Patrick Mcardle Mirjam Geerlings Yolanda van der Graaf Paul de Bakker Folkert Asselbergs Velandai Srikanth Russell Thomson Rebekah Mcwhirter Chris Moran Michele Callisaya Thanh Phan C Loes Steve Rutten-Jacobs Christophe Bevan Karen Mather Perminder Sachdev Cornelia van Duijn Bradford Worrall Martin Dichgans Steven Kittner Hugh Markus Mohammad Fmedsci Myriam Fornage Lenore Launer Sudha Seshadri W Longstreth Stéphanie Debette 1, *
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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Ganesh Chauhan, Hieab Adams, Claudia Satizabal, Joshua Bis, Alexander Teumer, et al.. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting. Neurology, American Academy of Neurology, 2019, 92 (5), pp.e486-e503. ⟨10.1212/WNL.0000000000006851⟩. ⟨inserm-02457571⟩

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