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; OR_{any 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.

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<1x10-6) and variants in linkage disequilibrium (r2>0.8)
• Supplementary Table 5. Independent genome-wide significant and suggestive associations (p<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<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<5x10-8) and suggestive (p<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