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Objective: We explored 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
sub-cortical BI (SSBI), in eighteen population-based cohorts (N=20,949)
from five ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were
followed up in seven population-based cohorts (N=6,862, 1,483 with BI, 630
with SBBI), and 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 nor 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. Conclusions: In this
multi-ethnic 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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