Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
PublisherLippincott Williams and Wilkins
MetadataShow full item record
AbstractObjective: 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. Copyright 2019 The Author(s).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85065551999&doi=10.1212%2fWNL.0000000000006851&partnerID=40&md5=f0508616ecee6ebb266b3f527b2ce5bf; http://hdl.handle.net/10713/10642
- Subcortical silent brain infarction as a risk factor for clinical stroke.
- Authors: Kobayashi S, Okada K, Koide H, Bokura H, Yamaguchi S
- Issue date: 1997 Oct
- Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.
- Authors: Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC).
- Issue date: 2016 Jun
- Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.
- Authors: Debette S, Bis JC, Fornage M, Schmidt H, Ikram MA, Sigurdsson S, Heiss G, Struchalin M, Smith AV, van der Lugt A, DeCarli C, Lumley T, Knopman DS, Enzinger C, Eiriksdottir G, Koudstaal PJ, DeStefano AL, Psaty BM, Dufouil C, Catellier DJ, Fazekas F, Aspelund T, Aulchenko YS, Beiser A, Rotter JI, Tzourio C, Shibata DK, Tscherner M, Harris TB, Rivadeneira F, Atwood LD, Rice K, Gottesman RF, van Buchem MA, Uitterlinden AG, Kelly-Hayes M, Cushman M, Zhu Y, Boerwinkle E, Gudnason V, Hofman A, Romero JR, Lopez O, van Duijn CM, Au R, Heckbert SR, Wolf PA, Mosley TH, Seshadri S, Breteler MM, Schmidt R, Launer LJ, Longstreth WT Jr
- Issue date: 2010 Feb
- The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk.
- Authors: Tragante V, Doevendans PA, Nathoe HM, van der Graaf Y, Spiering W, Algra A, de Borst GJ, de Bakker PI, Asselbergs FW, SMART study group.
- Issue date: 2013 Oct
- Suicidal Ideation
- Authors: Harmer B, Lee S, Duong TvH, Saadabadi A
- Issue date: 2021 Jan