Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database

Christina M Lill, Johannes T Roehr, Matthew B McQueen, Fotini K Kavvoura, Sachin Bagade, Brit-Maren M Schjeide, Leif M Schjeide, Esther Meissner, Ute Zauft, Nicole C Allen, Tian Liu, Marcel Schilling, Kari J Anderson, Gary Beecham, Daniela Berg, Joanna M Biernacka, Alexis Brice, Anita L DeStefano, Chuong B Do, Nicholas Eriksson, Stewart A Factor, Matthew J Farrer, Tatiana Foroud, Thomas Gasser, Taye Hamza, John A Hardy, Peter Heutink, Erin M Hill-Burns, Christine Klein, Jeanne C Latourelle, Demetrius M Maraganore, Eden R Martin, Maria Martinez, Richard H Myers, Michael A Nalls, Nathan Pankratz, Haydeh Payami, Wataru Satake, William K Scott, Manu Sharma, Andrew B Singleton, Kari Stefansson, Tatsushi Toda, Joyce Y Tung, Jeffery Vance, Nick W Wood, Cyrus P Zabetian, 23andMe Genetic Epidemiology of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Parkinson's Disease GWAS Consortium, Wellcome Trust Case Control Consortium 2), Peter Young, Rudolph E Tanzi, Muin J Khoury, Frauke Zipp, Hans Lehrach, John P A Ioannidis, Lars Bertram, Christina M Lill, Johannes T Roehr, Matthew B McQueen, Fotini K Kavvoura, Sachin Bagade, Brit-Maren M Schjeide, Leif M Schjeide, Esther Meissner, Ute Zauft, Nicole C Allen, Tian Liu, Marcel Schilling, Kari J Anderson, Gary Beecham, Daniela Berg, Joanna M Biernacka, Alexis Brice, Anita L DeStefano, Chuong B Do, Nicholas Eriksson, Stewart A Factor, Matthew J Farrer, Tatiana Foroud, Thomas Gasser, Taye Hamza, John A Hardy, Peter Heutink, Erin M Hill-Burns, Christine Klein, Jeanne C Latourelle, Demetrius M Maraganore, Eden R Martin, Maria Martinez, Richard H Myers, Michael A Nalls, Nathan Pankratz, Haydeh Payami, Wataru Satake, William K Scott, Manu Sharma, Andrew B Singleton, Kari Stefansson, Tatsushi Toda, Joyce Y Tung, Jeffery Vance, Nick W Wood, Cyrus P Zabetian, 23andMe Genetic Epidemiology of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Parkinson's Disease GWAS Consortium, Wellcome Trust Case Control Consortium 2), Peter Young, Rudolph E Tanzi, Muin J Khoury, Frauke Zipp, Hans Lehrach, John P A Ioannidis, Lars Bertram

Abstract

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.

Conflict of interest statement

CB Do, N Eriksson, and JY Tung are employed by 23andMe and own stock options in the company. MJ Farrer and Mayo Foundation received royalties from H.Lundbeck A/S and Isis Pharmaceuticals. In addition, MJ Farrer has received an honorarium for a seminar at Genzyme. T Gasser has received consultancy fees from Cephalon and Merck-Serono, grants from Novartis, payments for lectures including service on speakers' bureaus from Boehringer Ingelheim, Merck-Serono, UCB, and Valean, and holds patents NGFN2 and KASPP. JA Hardy has received consulting fees or honoraria from Eisai and his institute has received consulting fees or honoraria from Merck-Serono. DM Maraganore has received extramural research funding support from the National Institutes of Health (2R01 ES10751), the Michael J. Fox Foundation (Linked Efforts to Accelerate Parkinson Solutions Award, Edmond J. Safra Global Genetics Consortia Award), and from Alnylam Pharmaceuticals and Medtronic (observational studies of Parkinson's disease). DM Maraganore has also received intramural research funding support from the Mayo Clinic and from NorthShore University Health System. DM Maraganore filed a provisional patent for a method to predict Parkinson's disease. This provisional patent is unlicensed. He also filed a provisional patent for a method to treat neurodegenerative disorders. That provisional patent has been licensed to Alnylam Pharmaceuticals and DM Maraganore has received royalty payments in total of less than $20,000. K Stefansson has received grants from deCODE.

Figures

Figure 1. Manhattan plot of all meta-analysis…
Figure 1. Manhattan plot of all meta-analysis results performed in PDGene.
This summary combines association results from 7,123,986 random-effects meta-analyses based on the March 31st 2011 datafreeze of the PDGene database. Results are plotted as −log10P-values (y-axis) against physical chromosomal location (x-axis). Black and grey dots indicate results originating exclusively from the three fully publicly available GWAS datasets , , (see Methods), while green dots are based on a combination of smaller scale studies, supplemented by GWAS datasets (where applicable). Gene annotations are provided for genes highlighted in the main text.
Figure 2. Forest plot of the meta-analysis…
Figure 2. Forest plot of the meta-analysis of rs7077361 in ITGA8.
Study-specific allelic odds ratios (ORs, black squares) and 95% confidence intervals (CIs, lines) were calculated for each included dataset. The summary OR and CI was calculated using the DerSimonian Laird random-effects model (grey diamond) . C = Caucasian ancestry.
Figure 3. Flowchart of literature search, data…
Figure 3. Flowchart of literature search, data extraction, and analysis strategies applied for PDGene.

References

    1. de Lau LML, Breteler MMB. Epidemiology of Parkinson's disease. Lancet Neurol. 2006;5:525–535. doi: .
    1. Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C. The genetics of Parkinson's syndromes: a critical review. Curr Opin Genet Dev. 2009;19:254–265. doi: .
    1. Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, et al. VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011;89:162–167. doi: .
    1. Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011;89:168–175. doi: .
    1. Chartier-Harlin M-C, Dachsel JC, Vilariño-Güell C, Lincoln SJ, Leprêtre F, et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet. 2011;89:398–406. doi: .
    1. Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA. 2006;296:661–670. doi: .
    1. Zabetian CP, Yamamoto M, Lopez AN, Ujike H, Mata IF, et al. LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease. Mov Disord. 2009;24:1034–1041. doi: .
    1. Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJG, et al. Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol. 2007;62:145–153. doi: .
    1. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009;361:1651–1661. doi: .
    1. Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, et al. High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet. 2005;77:685–693. doi: .
    1. Fung H-C, Scholz S, Matarin M, Simón-Sánchez J, Hernandez D, et al. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 2006;5:911–916. doi: .
    1. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet. 2009;124:593–605. doi: .
    1. Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet. 2009;41:1308–1312. doi: .
    1. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet. 2009;41:1303–1307. doi: .
    1. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet. 2010;74:97–109. doi: .
    1. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. 2010;42:781–785. doi: .
    1. Spencer CCA, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, et al. Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet. 2011;20:345–353. doi: .
    1. Saad M, Lesage S, Saint-Pierre A, Corvol J-C, Zelenika D, et al. Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population. Hum Mol Genet. 2011;20:615–627. doi: .
    1. Simón-Sánchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, et al. Genome-wide association study confirms extant PD risk loci among the Dutch. Eur J Hum Genet. 2011;19:655–661. doi: .
    1. Evangelou E, Maraganore DM, Ioannidis JPA. Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease. PLoS ONE. 2007;2:e196. doi: .
    1. Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin U-M, et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377:641–649. doi: .
    1. Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet. 2011;7:e1002141. doi: .
    1. Sharma M, Ioannidis JPA, Aasly JO, Annesi G, Brice A, et al. Large-scale replication and heterogeneity in Parkinson disease genetic loci. n.d.. Neurology in press.
    1. Lin D-Y, Sullivan PF. Meta-analysis of genome-wide association studies with overlapping subjects. Am J Hum Genet. 2009;85:862–872. doi: .
    1. Ioannidis JPA. Effect of formal statistical significance on the credibility of observational associations. Am J Epidemiol. 2008;168:374–383; discussion 384–390. doi: .
    1. Ioannidis JPA, Boffetta P, Little J, O'Brien TR, Uitterlinden AG, et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol. 2008;37:120–132. doi: .
    1. Khoury MJ, Bertram L, Boffetta P, Butterworth AS, Chanock SJ, et al. Genome-wide association studies, field synopses, and the development of the knowledge base on genetic variation and human diseases. Am J Epidemiol. 2009;170:269–279. doi: .
    1. Kent WJ, Zweig AS, Barber G, Hinrichs AS, Karolchik D. BigWig and BigBed: enabling browsing of large distributed datasets. Bioinformatics. 2010;26:2204–2207. doi: .
    1. Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, et al. A survey of genetic human cortical gene expression. Nat Genet. 2007;39:1494–1499. doi: .
    1. Varnum-Finney B, Venstrom K, Muller U, Kypta R, Backus C, et al. The integrin receptor alpha 8 beta 1 mediates interactions of embryonic chick motor and sensory neurons with tenascin-C. Neuron. 1995;14:1213–1222.
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.
    1. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006;25:3443–3457. doi: .
    1. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39:17–23. doi: .
    1. Allen NC, Bagade S, McQueen MB, Ioannidis JPA, Kavvoura FK, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008;40:827–834. doi: .

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