Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

被引：37

作者：

Chauhan, Ganesh ^{[1
,3
]}

Adams, Hieab H. H. ^{[5
,6
]}

Satizabal, Claudia L. ^{[9
,11
,144
,145
]}

Bis, Joshua C. ^{[12
]}

Teumer, Alexander ^{[19
]}

Sargurupremraj, Muralidharan ^{[1
,3
]}

Hofer, Edith ^{[23
,24
]}

Trompet, Stella ^{[26
,27
]}

Hilal, Saima ^{[31
]}

Smith, Albert Vernon ^{[33
]}

Jian, Xueqiu ^{[34
]}

Malik, Rainer ^{[36
,137
]}

Traylor, Matthew ^{[37
]}

Pulit, Sara L. ^{[40
]}

Amouyel, Philippe ^{[45
]}

Mazoyer, Bernard ^{[2
,3
]}

Zhu, Yi-Cheng ^{[46
]}

Kaffashian, Sara ^{[1
,3
]}

Schilling, Sabrina ^{[1
,3
]}

Beecham, Gary W. ^{[47
]}

Montine, Thomas J. ^{[17
,18
]}

Schellenberg, Gerard D. ^{[52
]}

Kjartansson, Olafur ^{[53
,54
]}

Gudnason, Vilmundur ^{[33
,55
]}

Knopman, David S. ^{[56
]}

Griswold, Michael E. ^{[57
]}

Windham, B. Gwen ^{[58
]}

Gottesman, Rebecca F. ^{[59
]}

Mosley, Thomas H. ^{[58
]}

Schmidt, Reinhold ^{[23
]}

Saba, Yasaman ^{[25
]}

Schmidt, Helena ^{[25
]}

Takeuchi, Fumihiko ^{[60
]}

Yamaguchi, Shuhei ^{[61
]}

Nabika, Toru ^{[62
]}

Kato, Norihiro ^{[60
]}

Rajan, Kumar B. ^{[63
]}

Aggarwal, Neelum T. ^{[63
]}

De Jager, Philip L. ^{[65
]}

Evans, Denis A. ^{[63
]}

Psaty, Bruce M. ^{[12
,13
,14
,66
]}

Rotter, Jerome I. ^{[67
,68
,69
,70
,71
]}

Rice, Kenneth ^{[15
]}

Lopez, Oscar L. ^{[72
]}

Liao, Jiemin ^{[73
]}

Chen, Christopher ^{[31
]}

Cheng, Ching-Yu ^{[32
,74
,75
]}

Wong, Tien Y. ^{[74
,75
]}

Ikram, Mohammad K. ^{[31
,41
,74
,75
,76
]}

van der Lee, Sven J. ^{[77
]}

机构：

[1] Bordeaux Populat Hlth Res Ctr, Bordeaux, France

[2] CEA, CNRS, INSERM, U1219,Grp Imagerie Neurofonct,U5293, Bordeaux, France

[3] Univ Bordeaux, Bordeaux, France

[4] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France

[5] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[6] Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands

[7] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[8] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

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

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

[11] NHLBI, Framingham Heart Study, Bldg 10, Bethesda, MD 20892 USA

[12] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA

[13] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[14] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[15] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[16] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[17] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[18] Stanford Univ, Pathol, Stanford, CA 94305 USA

[19] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[20] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany

[21] Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany

[22] Univ Med Greifswald, Dept Neurol, Greifswald, Germany

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

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

[25] Med Univ Graz, Gottfried Schatz Res Ctr Cell Signaling Metab & A, Inst Mol Biol & Biochem, Graz, Austria

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

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

[28] Leiden Univ, Med Ctr, Mol Epidemiol, Leiden, Netherlands

[29] Leiden Univ, Med Ctr, Med Stat & Bioinformat, Leiden, Netherlands

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

[31] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore

[32] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore

[33] Icelandic Heart Assoc, Kopavogur, Iceland

[34] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA

[35] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[36] Ludwig Maximilians Univ Munchen, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany

[37] Univ Cambridge, Clin Neurosci, Cambridge, England

[38] Univ Lincoln, Sch Life Sci, Lincoln, England

[39] German Ctr Neurodegenerat Dis DZNE, Populat Hlth Sci, Bonn, Germany

[40] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[41] Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands

[42] Univ Med Ctr Utrecht, Dept Epidemiol, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[43] Univ Med Ctr Utrecht, Dept Genet, Ctr Mol Med, Utrecht, Netherlands

[44] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands

[45] Lille Univ, INSERM, Lille Univ Hosp, Inst Pasteur Lille, Lille, France

[46] Peking Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China

[47] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Coral Gables, FL 33124 USA

[48] Univ Miami, Miller Sch Med, Dept Neurol, Coral Gables, FL 33124 USA

[49] Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Coral Gables, FL 33124 USA

[50] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Coral Gables, FL 33124 USA

来源：

NEUROLOGY | 2019年 / 92卷 / 05期

基金：

欧洲研究理事会; 英国惠康基金; 英国生物技术与生命科学研究理事会; 奥地利科学基金会; 英国医学研究理事会; 欧盟地平线“2020”; 俄罗斯基础研究基金会; 澳大利亚国家健康与医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; MATTER HYPERINTENSITY VOLUME; SMALL VESSEL DISEASE; MENDELIAN RANDOMIZATION; ISCHEMIC-STROKE; BLOOD-PRESSURE; SILENT; METAANALYSIS; POLYMORPHISMS; INSIGHTS;

D O I：

10.1212/WNL.0000000000006851

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p([BI]) = 9.38 x 10(-25); p([SSBI]) = 5.23 x 10(-14) for hypertension), smoking (p([BI]) = 4.4 x 10(-10); p([SSBI]) = 1.2 x 10(-4)), diabetes (p([BI]) = 1.7 x 10(-8); p([SSBI]) = 2.8 x 10(-3)), previous cardiovascular disease (p([BI]) = 1.0 x 10(-18); p([SSBI]) = 2.3 x 10(-7)), stroke (p([BI]) = 3.9 x 10(-69); p([SSBI]) = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p([BI]) = 1.43 x 10(-157); p([SSBI]) = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

引用

页码：E486 / E503

页数：18

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