Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium

被引：70

作者：

Debette, Stephanie ^{[28
]}

Bis, Joshua C. ^{[19
]}

Fornage, Myriam ^{[6
,7
]}

Schmidt, Helena ^{[14
,17
]}

Ikram, M. Arfan ^{[32
,35
]}

Sigurdsson, Sigurdur ^{[2
]}

Heiss, Gerardo ^{[8
]}

Struchalin, Maksim ^{[18
]}

Smith, Albert V. ^{[2
]}

van der Lugt, Aad ^{[35
]}

DeCarli, Charles ^{[30
,31
,37
,38
]}

Lumley, Thomas ^{[20
]}

Knopman, David S. ^{[9
]}

Enzinger, Christian ^{[14
,16
]}

Eiriksdottir, Gudny ^{[2
]}

Koudstaal, Peter J. ^{[33
]}

DeStefano, Anita L. ^{[28
,29
]}

Psaty, Bruce M. ^{[19
,21
,22
,23
]}

Dufouil, Carole

Catellier, Diane J. ^{[10
]}

Fazekas, Franz ^{[14
]}

Aspelund, Thor ^{[2
,4
]}

Aulchenko, Yurii S. ^{[32
]}

Beiser, Alexa ^{[28
,29
]}

Rotter, Jerome I. ^{[25
]}

Tzourio, Christophe ^{[37
,38
]}

Shibata, Dean K. ^{[11
]}

Tscherner, Maria ^{[17
]}

Harris, Tamara B. ^{[5
]}

Rivadeneira, Fernando ^{[34
]}

Atwood, Larry D. ^{[28
]}

Rice, Kenneth ^{[20
]}

Gottesman, Rebecca F. ^{[12
]}

van Buchem, Mark A. ^{[3
]}

Uitterlinden, Andre G. ^{[34
,36
]}

Kelly-Hayes, Margaret ^{[28
]}

Cushman, Mary ^{[24
]}

Zhu, Yicheng ^{[37
,38
,39
,40
]}

Boerwinkle, Eric ^{[6
,7
]}

Gudnason, Vilmundur ^{[2
,4
]}

Hofman, Albert ^{[32
]}

Romero, Jose R. ^{[28
]}

Lopez, Oscar ^{[26
,27
]}

van Duijn, Cornelia M. ^{[32
]}

Au, Rhoda ^{[28
]}

Heckbert, Susan R. ^{[21
,23
]}

Wolf, Philip A. ^{[28
]}

Mosley, Thomas H. ^{[13
]}

Seshadri, Sudha ^{[28
]}

Breteler, Monique M. B. ^{[32
]}

机构：

[1] Univ Washington, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA

[2] Iceland Heart Assoc, Kopavogur, Iceland

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

[4] Univ Iceland, Reykjavik, Iceland

[5] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[6] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX USA

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

[8] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[9] Mayo Clin, Dept Neurol, Rochester, MN USA

[10] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[11] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98104 USA

[12] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

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

[14] Med Univ Graz, Dept Neurol, Graz, Austria

[15] Med Univ Graz, Dept Neurogeriatr, Graz, Austria

[16] Med Univ Graz, Dept Neuroradiol, Graz, Austria

[17] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[18] Erasmus MC Univ Med Ctr, Dept Epidemiol & Biostat, Dept Forens Mol Biol, Rotterdam, Netherlands

[19] Univ Washington, Dept Med, Seattle, WA 98104 USA

[20] Univ Washington, Dept Biostat, Seattle, WA 98104 USA

[21] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA

[22] Univ Washington, Dept Hlth Serv, Seattle, WA 98104 USA

[23] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA

[24] Univ Vermont, Dept Pathol & Med, Burlington, VT USA

[25] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[26] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA

[27] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA

[28] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[29] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

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

[31] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA

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

[33] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands

[34] Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[35] Erasmus MC Univ Med Ctr, Dept Radiol, Rotterdam, Netherlands

[36] Erasmus MC Univ Med Ctr, Dept Clin Chem, Rotterdam, Netherlands

[37] INSERM, U708, Paris, France

[38] Univ Paris 06, Paris, France

[39] Hop Lariboisiere, Serv Neurol, F-75475 Paris, France

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

来源：

STROKE | 2010年 / 41卷 / 02期

基金：

美国国家卫生研究院; 奥地利科学基金会;

关键词：

brain infarction; cohort study; genome-wide association study; meta-analysis; STROKE; FLRT3; ATHEROSCLEROSIS; PREVENTION; DISEASE; LESIONS; RISK;

D O I：

10.1161/STROKEAHA.109.569194

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2) > 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.)

引用

页码：210 / 217

页数：8

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