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Association of common genetic variants with brain microbleeds: A genome-wide association study

Research output: Contribution to journalArticle

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

Related Edinburgh Organisations

Original languageEnglish
JournalNeurology
DOIs
Publication statusPublished - 10 Sep 2020

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 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 haemorrhage 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.  

ID: 161618046