Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

被引：1505

作者：

Nalls, Mike A. ^{[1
]}

Pankratz, Nathan ^{[2
,21
]}

Lill, Christina M. ^{[3
,4
]}

Do, Chuong B. ^{[5
]}

Hernandez, Dena G. ^{[1
,6
]}

Saad, Mohamad ^{[7
,8
,9
]}

DeStefano, Anita L. ^{[10
,11
,12
]}

Kara, Eleanna ^{[13
]}

Bras, Jose ^{[13
]}

Sharma, Manu ^{[14
,15
]}

Schulte, Claudia ^{[15
]}

Keller, Margaux F. ^{[1
]}

Arepalli, Sampath ^{[1
]}

Letson, Christopher ^{[1
]}

Edsall, Connor ^{[1
]}

Stefansson, Hreinn ^{[16
]}

Liu, Xinmin ^{[17
]}

Pliner, Hannah ^{[1
]}

Lee, Joseph H. ^{[18
]}

Cheng, Rong ^{[18
]}

Ikram, M. Arfan ^{[19
,21
]}

Ioannidis, John P. A. ^{[22
]}

Hadjigeorgiou, Georgios M. ^{[23
]}

Bis, Joshua C. ^{[24
]}

Martinez, Maria ^{[8
,9
]}

Perlmutter, Joel S. ^{[25
,27
]}

Goate, Alison ^{[25
,27
,28
,29
]}

Marder, Karen ^{[18
,30
,31
,32
]}

Fiske, Brian ^{[33
]}

Sutherland, Margaret ^{[34
]}

Xiromerisiou, Georgia ^{[23
,35
]}

Myers, Richard H. ^{[10
]}

Clark, Lorraine N. ^{[17
,18
]}

Stefansson, Kari ^{[16
]}

Hardy, John A. ^{[6
]}

Heutink, Peter ^{[36
]}

Chen, Honglei

Wood, Nicholas W. ^{[13
]}

Houlden, Henry ^{[13
,19
,20
,21
]}

Payami, Haydeh ^{[22
,37
,38
]}

Brice, Alexis ^{[23
,39
,40
,41
]}

Scott, William K. ^{[24
,42
]}

Gasser, Thomas ^{[8
,9
,15
]}

Bertram, Lars ^{[3
,25
,26
,27
,43
]}

Eriksson, Nicholas ^{[5
]}

Foroud, Tatiana ^{[44
]}

Singleton, Andrew B. ^{[1
]}

机构：

[1] Natl Inst Aging, Lab Neurogenet, Bethesda, MD 20892 USA

[2] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[3] Max Planck Inst Mol Genet, Dept Vertebrate Gen, D-14195 Berlin, Germany

[4] Johannes Gutenberg Univ Mainz, Focus Program Translat Neurosci, Dept Neurol, D-55122 Mainz, Germany

[5] 23andMe Inc, Mountain View, CA USA

[6] UCL, Inst Neurol, Reta Lila Weston Inst, London, England

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

[8] Ctr Physiopathol Toulouse Purpan, INSERM, UMR 1043, Toulouse, France

[9] Univ Toulouse 3, F-31062 Toulouse, France

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

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

[12] Natl Heart Lung & Blood Inst NHLBI Framingham, Framingham, MA USA

[13] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[14] Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Tubingen, Germany

[15] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany

[16] deCODE Genet, Reykjavik, Iceland

[17] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA

[18] Columbia Univ, Med Ctr, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

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

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

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

[22] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA

[23] Univ Thessaly, Fac Med, Dept Neurol, Neurosci Unit, Larisa, Greece

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

[25] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA

[26] Washington Univ, Sch Med, Dept Radiol, St Louis, MO USA

[27] Washington Univ, Sch Med, Dept Neurol, St Louis, MO USA

[28] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[29] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[30] Columbia Univ, Med Ctr, Gertrude H Sergievsky Ctr, New York, NY USA

[31] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA

[32] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY USA

[33] Michael J Fox Fdn Parkinsons Res, New York, NY USA

[34] Natl Inst Neurol Disorders & Stroke, Neurosci Ctr, Bethesda, MD USA

[35] Papageorgiou Hosp, Dept Neurol, Thessaloniki, Greece

[36] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[37] NIEHS, Epidemiol Branch, US Natl Inst Hlth, Res Triangle Pk, NC 27709 USA

[38] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA

[39] Univ Paris 06, Sorbonne Univ, UM 75, INSERM U1127, Paris, France

[40] CNRS, UMR 7225, Paris, France

[41] Hop La Pitie Salpetriere, Dept Genet & Cytogenet, Paris, France

[42] Univ Miami, Sch Med, Dept Human Genet, Miami, FL USA

[43] Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, London, England

[44] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 09期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

PREDICTION; IMPUTATION; VARIANTS; REGION; GENES; HEART; SIZE;

D O I：

10.1038/ng.3043

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 x 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

引用

页码：989 / +

页数：7

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