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

被引：30

作者：

Knol, Maria J. ^{[1
]}

Lu, Dongwei ^{[4
]}

Traylor, Matthew ^{[4
]}

Adams, Hieab H. H. ^{[1
,2
,3
]}

Romero, Jose Rafael J. ^{[5
,6
]}

Smith, Albert, V ^{[7
,8
]}

Fornage, Myriam ^{[9
,10
]}

Hofer, Edith ^{[11
,12
]}

Liu, Junfeng ^{[4
,14
]}

Hostettler, Isabel C. ^{[15
,16
]}

Luciano, Michelle ^{[17
]}

Trompet, Stella ^{[19
,20
]}

Giese, Anne-Katrin ^{[25
]}

Hilal, Saima ^{[26
,27
,28
,29
]}

van den Akker, Erik B. ^{[21
,22
,30
]}

Vojinovic, Dina ^{[21
]}

Li, Shuo ^{[31
]}

Sigurdsson, Sigurdur ^{[8
]}

van der Lee, Sven J. ^{[1
]}

Jack, Clifford R., Jr. ^{[32
]}

Wilson, Duncan ^{[15
]}

Yilmaz, Pinar ^{[1
,2
]}

Satizabal, Claudia L. ^{[5
,6
,33
]}

Liewald, David C. M. ^{[17
]}

van der Grond, Jeroen ^{[20
,23
]}

Chen, Christopher ^{[26
,27
]}

Saba, Yasaman ^{[13
]}

van der Lugt, Aad ^{[2
]}

Bastin, Mark E. ^{[17
,18
]}

Windham, B. Gwen ^{[34
]}

Cheng, Ching Yu ^{[36
]}

Pirpamer, Lukas ^{[11
]}

Kantarci, Kejal ^{[32
]}

Himali, Jayandra J. ^{[5
,6
,31
]}

Yang, Qiong ^{[31
]}

Morris, Zoe ^{[37
]}

Beiser, Alexa S. ^{[5
,6
,31
]}

Tozer, Daniel J. ^{[4
]}

Vernooij, Meike W. ^{[1
,2
]}

Amin, Najaf ^{[1
]}

Beekman, Marian ^{[21
]}

Koh, Jia Yu ^{[36
]}

Stott, David J. ^{[38
]}

Houlden, Henry ^{[15
]}

Schmidt, Reinhold ^{[11
]}

Gottesman, Rebecca F. ^{[39
]}

MacKinnon, Andrew D. ^{[40
]}

DeCarli, Charles ^{[5
,41
]}

Gudnason, Vilmundur ^{[8
,44
]}

Deary, Ian J. ^{[17
]}

机构：

[1] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[2] Erasmus MC Univ Med Ctr, Dept Radiol & Nucl Med, Rotterdam, Netherlands

[3] Erasmus MC Univ Med Ctr, Dept Clin Genet, Rotterdam, Netherlands

[4] Univ Cambridge, Stroke Res Grp, Dept Clin Neurosci, Cambridge, England

[5] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA

[6] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[7] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[8] Iceland Heart Assoc, Kopavogur, Iceland

[9] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, McGovern Med Sch, Houston, TX 77030 USA

[10] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA

[11] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria

[12] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria

[13] Med Univ Graz, Gottfried Schatz Res Ctr, Dept Mol Biol & Biochem, Graz, Austria

[14] Sichuan Univ, West China Hosp, Ctr Cerebrovasc Dis, Dept Neurol, Chengdu, Sichuan, Peoples R China

[15] UCL, Stroke Res Ctr, Ctr Queen Sq Inst Neurol, London, England

[16] Univ Munich, Klinikum Rechts Isar, Dept Neurosurg, Munich, Germany

[17] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Psychol, Edinburgh, Midlothian, Scotland

[18] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh Imaging UK Dementia Res Inst, Edinburgh, Midlothian, Scotland

[19] Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands

[20] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands

[21] Leiden Univ, Med Ctr, Sect Mol Epidemiol Biomed Data Sci, Leiden, Netherlands

[22] Leiden Univ, Med Ctr, Leiden Computat Biol Ctr, Biomed Data Sci, Leiden, Netherlands

[23] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands

[24] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands

[25] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA

[26] Natl Univ Hlth Syst, Memory Aging & Cognit Ctr, Singapore, Singapore

[27] Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore

[28] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore

[29] Natl Univ Hlth Syst, Singapore, Singapore

[30] Delft Univ Technol, Pattern Recognit & Bioinformat, Delft, Netherlands

[31] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA

[32] Mayo Clin, Dept Radiol, Rochester, MN USA

[33] UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA

[34] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA

[35] Univ Mississippi, Med Ctr, Memory Impairment & Neurodegenerat Dementia MIND, Jackson, MS 39216 USA

[36] NHS Lothian, Singapore Eye Res Inst, Edinburgh, Midlothian, Scotland

[37] NHS Lothian, Dept Neuroradiol, Edinburgh, Midlothian, Scotland

[38] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[39] Johns Hopkins Univ, Div Cerebrovasc Neurol, Baltimore, MD USA

[40] St Georges NHS Fdn Trust, Atkinson Morley Neurosci Ctr, Dept Neuroradiol, London, England

[41] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA

[42] Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England

[43] NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA

[44] Univ Iceland, Fac Med, Reykjavik, Iceland

来源：

NEUROLOGY | 2020年 / 95卷 / 24期

关键词：

D O I：

10.1212/WNL.0000000000010852

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 epsilon 2 and epsilon 4 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 x 10(-10)). APOE epsilon 4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 x 10(-6)) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; p = 0.68). APOE epsilon 2 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 epsilon 4 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.

引用

页码：E3331 / E3343

页数：13

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