Genome-wide association study reveals genetic risk underlying Parkinson's disease

被引：1512

作者：

Simon-Sanchez, Javier ^{[2
,3
]}

Schulte, Claudia ^{[1
,4
]}

Bras, Jose M. ^{[2
,5
]}

Sharma, Manu ^{[1
,4
]}

Gibbs, J. Raphael ^{[2
,6
,7
]}

Berg, Daniela ^{[1
,4
]}

Paisan-Ruiz, Coro ^{[6
,7
]}

Lichtner, Peter ^{[8
]}

Scholz, Sonja W. ^{[2
,6
,7
]}

Hernandez, Dena G. ^{[2
,6
,7
]}

Krueger, Rejko

Federoff, Monica ^{[2
]}

Klein, Christine ^{[9
]}

Goate, Alison ^{[10
,11
]}

Perlmutter, Joel ^{[10
,11
]}

Bonin, Michael ^{[12
]}

Nalls, Michael A. ^{[2
]}

Illig, Thomas ^{[13
]}

Gieger, Christian ^{[13
]}

Houlden, Henry ^{[6
,7
]}

Steffens, Michael ^{[14
]}

Okun, Michael S. ^{[15
]}

Racette, Brad A. ^{[10
,11
]}

Cookson, Mark R. ^{[2
]}

Foote, Kelly D. ^{[15
]}

Fernandez, Hubert H. ^{[15
]}

Traynor, Bryan J. ^{[2
]}

Schreiber, Stefan ^{[16
]}

Arepalli, Sampath ^{[2
]}

Zonozi, Ryan ^{[2
]}

Gwinn, Katrina ^{[17
]}

van der Brug, Marcel ^{[2
,18
]}

Lopez, Grisel ^{[19
]}

Chanock, Stephen J. ^{[20
]}

Schatzkin, Arthur ^{[20
]}

Park, Yikyung ^{[20
]}

Hollenbeck, Albert ^{[21
]}

Gao, Jianjun ^{[22
]}

Huang, Xuemei ^{[23
,24
,25
,26
,27
,28
]}

Wood, Nick W. ^{[6
,7
]}

Lorenz, Delia ^{[29
]}

Deuschl, Guenther ^{[29
]}

Chen, Honglei ^{[22
]}

Riess, Olaf ^{[12
]}

Hardy, John A. ^{[6
,7
]}

Singleton, Andrew B. ^{[2
]}

Gasser, Thomas ^{[1
,4
]}

机构：

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

[2] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[3] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands

[4] German Ctr Neurodegenerat Dis, Tubingen, Germany

[5] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal

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

[7] UCL, Reta Lila Weston Labs, Inst Neurol, London, England

[8] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[9] Univ Lubeck, Dept Neurol, Sect Clin & Mol Neurogenet, Lubeck, Germany

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

[11] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[12] Univ Tubingen, Inst Human Genet, Dept Med Genet, Tubingen, Germany

[13] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[14] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany

[15] Univ Florida, Movement Disorders Ctr, Gainesville, FL USA

[16] Univ Kiel, Inst Klin Mol Biol, D-24098 Kiel, Germany

[17] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[18] Scripps Res Inst, Dept Neurosci, Scripps, FL USA

[19] NINDS, Parkinsons Dis Clin, NIH, Bethesda, MD 20892 USA

[20] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA

[21] AARP, Washington, DC USA

[22] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA

[23] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA

[24] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA

[25] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA

[26] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA

[27] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA

[28] Penn State Univ, Milton S Hershey Med Ctr, Dept Bioengn, Hershey, PA 17033 USA

[29] Univ Kiel, Neurol Klin, Univ Klinikum Schleswig Holstein, D-2300 Kiel, Germany

来源：

NATURE GENETICS | 2009年 / 41卷 / 12期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

PROGRESSIVE SUPRANUCLEAR PALSY; LINKAGE DISEQUILIBRIUM; TAU GENE; HAPLOTYPE; MUTATIONS; SYSTEM; SNCA;

D O I：

10.1038/ng.487

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

引用

页码：1308 / U68

页数：7

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