Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based study - Supplemental data

This file contains the supplemental data to the article entitled "Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based study". It contains additional methods paragraphs 1 to 4, supplemental tables 1 to 17, supplemental figures 1 to 7, and additional reference

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

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