22 Sep 20. Featured Paper

Association of common genetic variants with brain microbleeds: A Genome-wide Association Study

Link to paper on Neurology.

Authors

Maria J Knol, Dongwei Lu, Matthew Traylor, Hieab HH Adams, José Rafael J Romero,  Albert V Smith,  Myriam Fornage, Edith Hofer, Junfeng Liu, Isabel C Hostettler, Michelle Luciano, Stella Trompet, Anne-Katrin Giese, Saima Hilal, Erik B van den Akker, Dina Vojinovic, Shuo Li, Sigurdur Sigurdsson, Sven J van der Lee, Clifford R Jack, Duncan Wilson, Pinar Yilmaz, Claudia L Satizabal, David C.M. Liewald, Jeroen van der Grond, Christopher Chen, Yasaman Saba, Aad van der Lugt, Mark E Bastin, B Gwen Windham, Ching Yu Cheng, Lukas Pirpamer, Kejal Kantarci, Jayandra J Himali, Qiong Yang, Zoe Morris, Alexa S Beiser, Daniel J Tozer, Meike W Vernooij, Najaf Amin, Marian Beekman, Jia Yu Koh, David J Stott, Henry Houlden, Reinhold Schmidt, Rebecca F Gottesman, Andrew D MacKinnon, Charles DeCarli, Vilmundur Gudnason, Ian J Deary, Cornelia M van Duijn, P Eline Slagboom, Tien Yin Wong, Natalia S Rost, J Wouter Jukema, Thomas H Mosley, David J Werring, Helena Schmidt, Joanna M Wardlaw, M Arfan Ikram, Sudha Seshadri, Lenore J Launer, Hugh S Markus, for the Alzheimer’s Disease Neuroimaging Initiative

Abstract

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 & 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, & further classified as lobar, or mixed (including strictly deep & infratentorial, possibly with lobar BMB).

In a subset, we assessed the effects of APOE ε2 & 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 & 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 haemorrhage & lacunar stroke, & 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.

Keywords

• Association studies in genetics

• MRI

• Other cerebrovascular disease/ Stroke