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

TitleGenetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.
Publication TypeJournal Article
Year of Publication2019
AuthorsChauhan G, Adams HHH, Satizabal CL, et al.
Secondary AuthorsDebette S
Corporate AuthorsStroke 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) C
JournalNeurology
Date Published2019 Jan 16
ISSN1526-632X
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, = 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.

DOI10.1212/WNL.0000000000006851
Alternate JournalNeurology
PubMed ID30651383
PubMed Central IDPMC6369905
Grant ListP30 AG053760 / AG / NIA NIH HHS / United States
UH3 NS100605 / NS / NINDS NIH HHS / United States
R01 NS087541 / NS / NINDS NIH HHS / United States
P01 AG000538 / AG / NIA NIH HHS / United States
RF1 AG051504 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom
KL2 TR001429 / TR / NCATS NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 AG015819 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
MR/J006971/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 NS083633 / NS / NINDS NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
G1100540 / MRC_ / Medical Research Council / United Kingdom
RF1 AG059421 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
MR/M013111/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG017917 / AG / NIA NIH HHS / United States
G1001245 / MRC_ / Medical Research Council / United Kingdom
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
P30 AG012300 / AG / NIA NIH HHS / United States
R01 AG061796 / AG / NIA NIH HHS / United States
G0701120 / MRC_ / Medical Research Council / United Kingdom
U01 AG052409 / AG / NIA NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States