Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium

被引：164

作者：

Fornage, Myriam ^{[1
,2
]}

Debette, Stephanie ^{[3
]}

Bis, Joshua C. ^{[4
,5
]}

Schmidt, Helena ^{[6
]}

Ikram, M. Arfan ^{[7
,8
]}

Dufouil, Carole ^{[9
,10
]}

Sigurdsson, Sigurdur ^{[11
]}

Lumley, Thomas ^{[12
]}

DeStefano, Anita L. ^{[3
,13
]}

Fazekas, Franz ^{[14
]}

Vrooman, Henri A. ^{[7
,15
,16
]}

Shibata, Dean K. ^{[17
]}

Maillard, Pauline ^{[18
,19
]}

Zijdenbos, Alex ^{[20
,21
]}

Smith, Albert V. ^{[11
]}

Gudnason, Haukur ^{[11
]}

de Boer, Renske ^{[7
,8
,15
,16
]}

Cushman, Mary ^{[22
]}

Mazoyer, Bernard ^{[18
,19
]}

Heiss, Gerardo ^{[23
]}

Vernooij, Meike W. ^{[7
,8
]}

Enzinger, Christian ^{[14
]}

Glazer, Nicole L. ^{[4
,5
]}

Beiser, Alexa ^{[3
,13
]}

Knopman, David S. ^{[24
]}

Cavalieri, Margherita ^{[14
,25
]}

Niessen, Wiro J. ^{[15
,16
]}

Harris, Tamara B. ^{[26
]}

Petrovic, Katja ^{[14
]}

Lopez, Oscar L. ^{[27
,28
]}

Au, Rhoda ^{[3
]}

Lambert, Jean-Charles ^{[29
]}

Hofman, Albert ^{[7
]}

Gottesman, Rebecca F. ^{[30
]}

Garcia, Melissa ^{[26
]}

Heckbert, Susan R. ^{[31
,32
]}

Atwood, Larry D. ^{[3
]}

Catellier, Diane J. ^{[33
]}

Uitterlinden, Andre G. ^{[7
,34
,35
]}

Yang, Qiong ^{[13
]}

Smith, Nicholas L. ^{[31
,36
]}

Aspelund, Thor ^{[11
,37
]}

Romero, Jose R. ^{[3
]}

Rice, Kenneth ^{[12
]}

Taylor, Kent D. ^{[38
]}

Nalls, Michael A. ^{[39
]}

Rotter, Jerome I. ^{[38
]}

Sharrett, Richey ^{[30
]}

van Duijn, Cornelia M. ^{[7
]}

Amouyel, Philippe ^{[29
]}

机构：

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

[2] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Div Epidemiol, Sch Publ Hlth, Houston, TX USA

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

[4] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[5] Univ Washington, Dept Med, Seattle, WA USA

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

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

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

[9] Hop La Pitie Salpetriere, INSERM, U708, Paris, France

[10] Univ Paris 06, Paris, France

[11] Iceland Heart Assoc, Kopavogur, Iceland

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

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

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

[15] Erasmus MC Univ Med Ctr, Dept Med Informat, Rotterdam, Netherlands

[16] Erasmus MC Univ Med Ctr, Biomed Imaging Grp Rotterdam, Rotterdam, Netherlands

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

[18] Univ Caen Basse Normandie, Caen, France

[19] Ctr Energie Atom, Ctr Natl Rech Sci, Grp Imagerie Neurofonct, Caen, France

[20] Biospective Inc, Montreal, PQ, Canada

[21] McGill Univ, Neurol Inst, Montreal, PQ, Canada

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

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

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

[25] Univ Ferrara, Dept Clin & Expt Med, Sect Internal Med Gerontol & Geriatr, I-44100 Ferrara, Italy

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

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

[28] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[29] Inst Pasteur, INSERM, U744, F-59019 Lille, France

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

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

[32] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

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

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

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

[36] Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA

[37] Univ Iceland, Reykjavik, Iceland

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

[39] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA

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

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

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

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

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

来源：

ANNALS OF NEUROLOGY | 2011年 / 69卷 / 06期

关键词：

HYPERINTENSITY VOLUME; GENE; LEUKOARAIOSIS; PROTEIN; LOCI; HEART;

D O I：

10.1002/ana.22403

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. Methods: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. Results: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 x 10(-9); p(replication) = 1.3 x 10(-7); p(combined) = 4.0 x 10(-15)). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 x 10(-9)), rs11869977 (p = 5.7 x 10(-9)), rs936393 (p = 6.8 x 10(-9)), rs3744017 (p = 7.3 x 10(-9)), and rs1055129 (p = 4.1 x 10(-8)). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). Interpretation: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH. ANN NEUROL 2011;69:928-939

引用

页码：928 / 939

页数：12

共 33 条

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