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

Maria J Knol; Dongwei Lu; Matthew Traylor; Hieab H H 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 Jr; 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; Alzheimer's Disease Neuroimaging Initiative

doi:10.1212/WNL.0000000000010852

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

Neurology. 2020 Dec 15;95(24):e3331-e3343. doi: 10.1212/WNL.0000000000010852. Epub 2020 Sep 10.

Authors

Maria J Knol^{1

2}, Dongwei Lu^{1

2}, Matthew Traylor^{1

2}, Hieab H H Adams^{1

2}, José Rafael J Romero^{1

2}, Albert V Smith^{1

2}, Myriam Fornage^{1

2}, Edith Hofer^{1

2}, Junfeng Liu^{1

2}, Isabel C Hostettler^{1

2}, Michelle Luciano^{1

2}, Stella Trompet^{1

2}, Anne-Katrin Giese^{1

2}, Saima Hilal^{1

2}, Erik B van den Akker^{1

2}, Dina Vojinovic^{1

2}, Shuo Li^{1

2}, Sigurdur Sigurdsson^{1

2}, Sven J van der Lee^{1

2}, Clifford R Jack Jr^{1

2}, Duncan Wilson^{1

2}, Pinar Yilmaz^{1

2}, Claudia L Satizabal^{1

2}, David C M Liewald^{1

2}, Jeroen van der Grond^{1

2}, Christopher Chen^{1

2}, Yasaman Saba^{1

2}, Aad van der Lugt^{1

2}, Mark E Bastin^{1

2}, B Gwen Windham^{1

2}, Ching Yu Cheng^{1

2}, Lukas Pirpamer^{1

2}, Kejal Kantarci^{1

2}, Jayandra J Himali^{1

2}, Qiong Yang^{1

2}, Zoe Morris^{1

2}, Alexa S Beiser^{1

2}, Daniel J Tozer^{1

2}, Meike W Vernooij^{1

2}, Najaf Amin^{1

2}, Marian Beekman^{1

2}, Jia Yu Koh^{1

2}, David J Stott^{1

2}, Henry Houlden^{1

2}, Reinhold Schmidt^{1

2}, Rebecca F Gottesman^{1

2}, Andrew D MacKinnon^{1

2}, Charles DeCarli^{1

2}, Vilmundur Gudnason^{1

2}, Ian J Deary^{1

2}, Cornelia M van Duijn^{1

2}, P Eline Slagboom^{1

2}, Tien Yin Wong^{1

2}, Natalia S Rost^{1

2}, J Wouter Jukema^{1

2}, Thomas H Mosley^{1

2}, David J Werring^{1

2}, Helena Schmidt^{1

2}, Joanna M Wardlaw^{1

2}, M Arfan Ikram^{1

2}, Sudha Seshadri^{1

2}, Lenore J Launer^{3

4}, Hugh S Markus^{3

4}; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ 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 Iceland, Reykjavik, Iceland.
² Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found in the coinvestigators list at links.lww.com/WNL/B222.
³ 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 Iceland, Reykjavik, Iceland. [email protected] [email protected].
⁴ Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found in the coinvestigators list at links.lww.com/WNL/B222. [email protected] [email protected].

Abstract

Objective: To identify common genetic variants associated with the presence of brain microbleeds (BMBs).

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. 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.

Results: BMBs 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.

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 BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alleles
Apolipoprotein E2 / genetics
Apolipoprotein E4 / genetics*
Apolipoproteins E / genetics*
Case-Control Studies
Cerebral Hemorrhage / diagnostic imaging
Cerebral Hemorrhage / epidemiology
Cerebral Hemorrhage / genetics*
Cerebral Hemorrhage / pathology*
Cerebral Small Vessel Diseases / epidemiology
Cerebral Small Vessel Diseases / genetics*
Cohort Studies
Female
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Polymorphism, Single Nucleotide
Risk
White Matter / diagnostic imaging
White Matter / pathology*

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

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