A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

被引：192

作者：

Plagnol, Vincent ^{[1
]}

Nalls, Michael A. ^{[2
]}

Bras, Jose M. ^{[3
]}

Hernandez, Dena G. ^{[2
,3
]}

Sharma, Manu ^{[4
]}

Sheerin, Una-Marie ^{[3
]}

Saad, Mohamad ^{[4
,5
]}

Simon-Sanchez, Javier ^{[6
]}

Schulte, Claudia ^{[7
,8
]}

Lesage, Suzanne ^{[9
,10
,11
]}

Sveinbjornsdottir, Sigurlaug ^{[12
,13
,14
]}

Amouyel, Philippe ^{[15
,16
]}

Arepalli, Sampath ^{[1
]}

Band, Gavin ^{[17
]}

Barker, Roger A. ^{[18
]}

Bellinguez, Celine ^{[17
]}

Ben-Shlomo, Yoav ^{[19
]}

Berendse, Henk W. ^{[20
,21
]}

Berg, Daniela ^{[7
,8
]}

Bhatia, Kailash ^{[22
]}

de Bie, Rob M. A. ^{[23
]}

Biffi, Alessandro ^{[24
,25
,26
]}

Bloem, Bas ^{[27
]}

Bochdanovits, Zoltan ^{[6
]}

Bonin, Michael ^{[28
]}

Brockmann, Kathrin ^{[7
,8
]}

Brooks, Janet ^{[1
]}

Burn, David J. ^{[29
]}

Charlesworth, Gavin ^{[3
]}

Chen, Honglei ^{[30
]}

Chinnery, Patrick F. ^{[31
]}

Chong, Sean ^{[2
]}

Clarke, Carl E. ^{[32
,33
]}

Cookson, Mark R. ^{[2
]}

Cooper, J. Mark ^{[34
]}

Corvol, Jean Christophe ^{[9
,10
,11
,35
]}

Counsell, Carl ^{[36
]}

Damier, Philippe ^{[37
]}

Dartigues, Jean-Francois ^{[38
]}

Deloukas, Panos ^{[39
]}

Deuschl, Guenther ^{[40
]}

Dexter, David T. ^{[41
]}

van Dijk, Karin D. ^{[20
,21
]}

Dillman, Allissa ^{[2
]}

Durif, Frank ^{[42
]}

Duerr, Alexandra ^{[8
,9
,10
,43
]}

Edkins, Sarah ^{[39
]}

Evans, Jonathan R. ^{[44
]}

Foltynie, Thomas

Freeman, Colin ^{[17
]}

机构：

[1] UCL, UCL Genet Inst, London, England

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

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

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

[5] Univ Toulouse 3, Toulouse, France

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

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

[8] German Ctr Neurodegenerat Dis, Deutsch Zentrum Neurodegenerat Erkrangungen, Tubingen, Germany

[9] INSERM, UMR S975, Paris, France

[10] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelleepiniere, UMR S975, Paris, France

[11] CNRS, UMR 7225, Paris, France

[12] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland

[13] Broomfield Hosp, Mid Essex Hosp, Dept Neurol, Chelmsford, Essex, England

[14] Univ London, Queen Mary Coll, London, England

[15] INSERM, U744, F-59045 Lille, France

[16] Univ Lille Nord, Inst Pasteur Lille, Lille, France

[17] Wellcome Trust Ctr Human Genet, Oxford, England

[18] Univ Cambridge, Addenbrookes Hosp, Dept Neurol, Cambridge CB2 2QQ, England

[19] Univ Bristol, Dept Social Med, Bristol, Avon, England

[20] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands

[21] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands

[22] UCL, Inst Neurol, Dept Motor Neurosci, London, England

[23] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands

[24] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[25] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[26] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[27] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 ED Nijmegen, Netherlands

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

[29] Newcastle Univ, Clin Ageing Res Unit, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

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

[31] Newcastle Univ, Dept Neurol, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[32] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England

[33] W Birmingham Hosp NHS Trust, Birmingham, W Midlands, England

[34] UCL, Inst Neurol, Dept Clin Neurosci, London, England

[35] Hop La Pitie Salpetriere, INSERM, CIC 9503, Paris, France

[36] Univ Aberdeen, Div Appl Hlth Sci, Populat Hlth Sect, Aberdeen, Scotland

[37] CHU Nantes, CIC0004, Serv Neurol, F-44035 Nantes 01, France

[38] Univ Victor Segalen, INSERM, U897, Bordeaux, France

[39] Wellcome Trust Sanger Inst, Cambridge, England

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

[41] Univ London Imperial Coll Sci Technol & Med, Parkinsons Dis Res Grp, Fac Med, London, England

[42] Hop Gabriel Montpied, Serv Neurol, Clermont Ferrand, France

[43] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France

[44] Univ Cambridge, Cambridge Ctr Brain Repair, Cambridge, England

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

[46] 14 DeCODE Genet, Reykjavik, Iceland

[47] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands

[48] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[49] Amer Assoc Retired Persons, Washington, DC USA

[50] UCL, Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England

来源：

PLOS GENETICS | 2011年 / 7卷 / 06期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

FIBROBLAST-GROWTH-FACTOR; GENOME-WIDE ASSOCIATION; GENE; MUTATIONS; RISK; HAPLOTYPES; VARIANTS; SEQUENCE; LINKAGE; CLONING;

D O I：

10.1371/journal.pgen.1002142

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5x10(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci.

引用

页数：9

共 35 条

[1] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[2] Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism [J].

Bonifati, V ;

Rizzu, P ;

van Baren, MJ ;

Schaap, O ;

Breedveld, GJ ;

Krieger, E ;

Dekker, MCJ ;

Squitieri, F ;

Ibanez, P ;

Joosse, M ;

van Dongen, JW ;

Vanacore, N ;

van Swieten, JC ;

Brice, A ;

Meco, G ;

van Duijn, CM ;

Oostra, BA ;

Heutink, P .

SCIENCE, 2003, 299 (5604) :256-259

[3]

Cabin DE, 2002, J NEUROSCI, V22, P8797

[4] Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients -: art. no. 11 [J].

Clarimon, J ;

Xiromerisiou, G ;

Eerola, J ;

Gourbali, V ;

Hellström, O ;

Dardiotis, E ;

Peuralinna, T ;

Papadimitriou, A ;

Hadjigeorgiou, GM ;

Tienari, PJ ;

Singleton, AB .

BMC NEUROLOGY, 2005, 5 (1)

[5] Rare Variants Create Synthetic Genome-Wide Associations [J].

Dickson, Samuel P. ;

Wang, Kai ;

Krantz, Ian ;

Hakonarson, Hakon ;

Goldstein, David B. .

PLOS BIOLOGY, 2010, 8 (01)

[6] Common LRRK2 mutation in idiopathic Parkinson's disease [J].

Gilks, WP ;

Abou-Sleiman, PM ;

Gandhi, S ;

Jain, S ;

Singleton, A ;

Lees, AJ ;

Shaw, K ;

Bhatia, KP ;

Bonifati, V ;

Quinn, NP ;

Lynch, J ;

Healy, DG ;

Holton, JL ;

Revesz, T ;

Wood, NW .

LANCET, 2005, 365 (9457) :415-416

[7] Characterisation of the NUCKS gene on human chromosome 1q32.1 and the presence of a homologous gene in different species [J].

Grundt, K ;

Haga, IV ;

Aleporou-Marinou, V ;

Drosos, Y ;

Wanvik, B ;

Ostvold, AC .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 323 (03) :796-801

[8] Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease [J].

Hamza, Taye H. ;

Zabetian, Cyrus P. ;

Tenesa, Albert ;

Laederach, Alain ;

Montimurro, Jennifer ;

Yearout, Dora ;

Kay, Denise M. ;

Doheny, Kimberly F. ;

Paschall, Justin ;

Pugh, Elizabeth ;

Kusel, Victoria I. ;

Collura, Randall ;

Roberts, John ;

Griffith, Alida ;

Samii, Ali ;

Scott, William K. ;

Nutt, John ;

Factor, Stewart A. ;

Payami, Haydeh .

NATURE GENETICS, 2010, 42 (09) :781-U75

[9] Pruning and loss of excitatory synapses by the parkin ubiquitin ligase [J].

Helton, Thomas D. ;

Otsuka, Takeshi ;

Lee, Ming-Chia ;

Mu, Yuanyue ;

Ehlers, Michael D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (49) :19492-19497

[10]

Jeffers M, 2001, CANCER RES, V61, P3131

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