Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Accept all cookies Reject all non-essential cookies

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

Knol MJ., Lu D., Traylor M., Adams HHH., Romero JRJ., Smith AV., Fornage M., Hofer E., Liu J., Hostettler IC., Luciano M., Trompet S., Giese A-K., Hilal S., van den Akker EB., Vojinovic D., Li S., Sigurdsson S., van der Lee SJ., Jack CR., Wilson D., Yilmaz P., Satizabal CL., Liewald DCM., van der Grond J., Chen C., Saba Y., van der Lugt A., Bastin ME., Windham BG., Cheng CY., Pirpamer L., Kantarci K., Himali JJ., Yang Q., Morris Z., Beiser AS., Tozer DJ., Vernooij MW., Amin N., Beekman M., Koh JY., Stott DJ., Houlden H., Schmidt R., Gottesman RF., MacKinnon AD., DeCarli C., Gudnason V., Deary IJ., van Duijn CM., Slagboom PE., Wong TY., Rost NS., Jukema JW., Mosley TH., Werring DJ., Schmidt H., Wardlaw JM., Ikram MA., Seshadri S., Launer LJ., Markus HS., Alzheimer's Disease Neuroimaging Initiative None.

ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe 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. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI 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 BMBs.ResultsBMBs 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 single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21-1.45]; p = 2.5 × 10-10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10-6) 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.ConclusionsGenetic 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 BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

Original publication

DOI

10.1212/wnl.0000000000010852

Type

Journal article

Journal

Neurology

Publication Date

12/2020

Volume

95

Pages

e3331 - e3343

Addresses

From the Departments of Epidemiology (M.J.K., H.H.H.A., D.V., S.J.v.d.L., P.Y., M.W.V., N.A., C.M.v.D., M.A.I.), Radiology and Nuclear Medicine (H.H.H.A., P.Y., A.v.d.L., M.W.V.), and Clinical Genetics (H.H.H.A.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Stroke Research Group, Department of Clinical Neurosciences (D.L., M.T., J.L., D.J.T., H.S.M.), University of Cambridge, UK; Department of Neurology (J.R.J.R., C.L.S., J.J.H., A.S.B., C.D., S. Seshadri), Boston University School of Medicine; The Framingham Heart Study (J.R.J.R., C.L.S., J.J.H., A.S.B., S. Seshadri), MA; Department of Biostatistics (A.V.S.), University of Michigan, Ann Arbor; Icelandic Heart Association (A.V.S., S. Sigurdsson, V.G.), Kopavogur, Iceland; Brown Foundation Institute of Molecular Medicine, McGovern Medical School (M.F.), and Human Genetics Center, School of Public Health (M.F.), University of Texas Health Science Center at Houston; Clinical Division of Neurogeriatrics, Department of Neurology (E.H., L.P., R.S.), Institute for Medical Informatics, Statistics and Documentation (E.H.), and Gottfried Schatz Research Center, Department of Molecular Biology and Biochemistry (Y.S., H.S.), Medical University of Graz, Austria; Center of Cerebrovascular Diseases, Department of Neurology (J.L.), West China Hospital, Sichuan University, Chengdu; Stroke Research Centre, Queen Square Institute of Neurology (I.C.H., D.W., H.H., D.J.W.), University College London, UK; Department of Neurosurgery (I.C.H.), Klinikum rechts der Isar, University of Munich, Germany; Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology (M.L., D.C.M.L., M.E.B., I.J.D., J.M.W.), and Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute (M.E.B., J.M.W.), University of Edinburgh, UK; Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Department of Cardiology (S.T., J.v.d.G., J.W.J.), Section of Molecular Epidemiology, Biomedical Data Sciences (E.B.v.d.A., M.B., P.E.S.), Leiden Computational Biology Center, Biomedical Data Sciences (E.B.v.d.A.), Department of Radiology (J.v.d.G.), and Einthoven Laboratory for Experimental Vascular Medicine (J.W.J.), Leiden University Medical Center, the Netherlands; Department of Neurology (A.-K.G., N.S.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Memory Aging and Cognition Center (S.H., C.C.), National University Health System, Singapore; Department of Pharmacology (S.H., C.C.) and Saw Swee Hock School of Public Health (S.H.), National University of Singapore and National University Health System, Singapore; Pattern Recognition & Bioinformatics (E.B.v.d.A.), Delft University of Technology, the Netherlands; Department of Biostatistics (S.L., J.J.H., Q.Y., A.S.B.), Boston University School of Public Health, MA; Department of Radiology (C.R.J., K.K.), Mayo Clinic, Rochester, MN; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S. Seshadri), UT Health San Antonio, TX; Department of Medicine, Division of Geriatrics (B.G.W., T.H.M), and Memory Impairment and Neurodegenerative Dementia (MIND) Center (T.H.M.), University of Mississippi Medical Center, Jackson; Singapore Eye Research Institute (C.Y.C., J.Y.K., T.Y.W.); Department of Neuroradiology (Z.M., J.M.W.), NHS Lothian, Edinburgh; Institute of Cardiovascular and Medical Sciences (D.J.S.), College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; Division of Cerebrovascular Neurology (R.F.G.), Johns Hopkins University, Baltimore, MD; Department of Neuroradiology (A.D.M.), Atkinson Morley Neurosciences Centre, St George's NHS Foundation Trust, London, UK; Department of Neurology (C.D.), University of California at Davis; Nuffield Department of Population Health (C.M.v.D.), University of Oxford, UK; Laboratory of Epidemiology and Population Sciences (L.J.L.), National Institute on Aging, Baltimore, MD; and Faculty of Medicine (V.G.), University of

Keywords

Alzheimer's Disease Neuroimaging Initiative, Humans, Cerebral Hemorrhage, Genetic Predisposition to Disease, Apolipoproteins E, Magnetic Resonance Imaging, Risk, Case-Control Studies, Cohort Studies, Polymorphism, Single Nucleotide, Alleles, Aged, Aged, 80 and over, Middle Aged, Female, Male, Apolipoprotein E2, Apolipoprotein E4, Genome-Wide Association Study, Cerebral Small Vessel Diseases, White Matter