DOI: 10.5061/dryad.mcvdncjz4
title: Association of common genetic variants with brain microbleeds: A genome-wide association study

description: Objective: To identify common genetic variants associated with the
 presence of brain microbleeds (BMB). Methods: We performed genome-wide
 association studies in 11 population-based cohort studies and 3
 case-control or case-only stroke cohorts. Genotypes were imputed to the
 Haplotype Reference Consortium or 1000 Genomes reference panel. BMB were
 rated on susceptibility-weighted or T2*-weighted gradient echo magnetic
 resonance imaging sequences, and further classified as lobar, or mixed
 (including strictly deep and infratentorial, possibly with lobar BMB). In
 a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts.
 We also related previously identified cerebral small vessel disease
 variants to BMB. Results: BMB were detected in 3,556 of the 25,862
 participants, of which 2,179 were strictly lobar and 1,293 mixed. One
 locus in the APOE region reached genome-wide significance for its
 association with BMB (lead SNP rs769449; ORany BMB (95% CI)=1.33
 (1.21-1.45); p=2.5x10-10). APOE ε4 alleles were associated with strictly
 lobar (OR (95% CI)=1.34 (1.19- 1.50); p=1.0x10-6) but not with mixed BMB
 counts (OR (95% CI)=1.04 (0.86-1.25); p=0.68). APOE ε2 alleles did not
 show associations with BMB counts. Variants previously related to deep
 intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral
 white matter hyperintensity variants, were associated with BMB.
 Conclusions: Genetic variants in the APOE region are associated with the
 presence of BMB, most likely due to the APOE ε4 allele count related to a
 higher number of strictly lobar BMB. Genetic predisposition to small
 vessel disease confers risk of BMB, indicating genetic overlap with other
 cerebral small vessel disease markers.
description: Supplementary Material belonging to the publication
 'Association of common genetic variants with brain microbleeds: A
 genome-wide association study' Files
 include: Supplementary Tables 
 Supplementary Table 1. Genotyping and quality control
 metrics Supplementary Table 2. Image data acquisition
 and processing Supplementary Table 3. Genomic
 inflation and polygenicity in the different meta-analyses
 Supplementary Table 4. Functional annotation of genome-wide
 significant and suggestive genetic variants for brain microbleeds
 (p&lt;1x10-6) and variants in linkage disequilibrium
 (r2&gt;0.8) Supplementary Table 5. Independent
 genome-wide significant and suggestive associations (p&lt;1x10-6) with
 brain microbleeds in a sample excluding individuals with dementia or
 stroke Supplementary Table 6. The effects of APOE ε4
 allele count on the number of brain microbleeds overall and by location,
 excluding individuals with the APOE ε2ε4 genotype
 Supplementary Table 7. Association of genetic variants for
 Alzheimer’s disease and stroke with brain microbleeds overall and by
 location Supplementary Figures
 Supplementary Figure 1. Quantile-quantile plots
 showing the observed versus expected –log P-value for (A) any, (B) lobar
 and (C) mixed microbleeds Supplementary Figure 2.
 Regional plots of the suggestive genetic variants (p&lt;1x10-6) for
 overall or location-specific microbleeds
 Supplementary Figure 3. Forest plots showing the study-specific
 associations between the independent genome-wide significant
 (p&lt;5x10-8) and suggestive (p&lt;1x10-6) genetic variants and
 brain microbleeds, overall and by location
 Supplementary Figure 4. Quantile-quantile plots and Manhattan
 plots presenting the results of the genome-wide association studies of (A)
 any, (B) lobar, and (C) mixed microbleeds in a study sample without
 dementia or stroke Supplementary
 Information Supplementary
 methods Acknowledgments and funding