A1 Refereed original research article in a scientific journal
Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
Authors: 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
Publication year: 2019
Journal: Neurology
Volume: 92
Issue: 5
First page : e486
Last page: e503
Number of pages: 18
ISSN: 0028-3878
DOI: https://doi.org/10.1212/WNL.0000000000006851
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/44203189
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.
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.
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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