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GWAS-linked GAK locus in Parkinson’s disease in Han Chinese and meta-analysis

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Abstract

Genome-wide association studies of Parkinson’s disease (PD) have recently identified a new susceptibility locus GAK (PARK17) (rs1564282 variant) in subjects of European ancestry. Its role in other races is still unclear. The potential differences of the clinical characteristics between carriers and non-carriers have not been examined in detail. Using a case–control methodology, we analyzed the GAK rs1564282 variant in an ethnic Han Chinese population and conducted a meta-analysis combining our result and available published data. A total of 1,574 ethnic Han Chinese study subjects comprising 812 sporadic PD patients and 762 control individuals were included. The minor allele frequency was significantly different at SNP rs1564282 between the cases and the controls (OR = 1.59, 95% CI = 1.09, 1.69, P = 0.007) in the overall PD population. Subjects with CT + TT genotypes have an increased risk (OR = 1.34, 95% CI = 1.05, 1.72, P = 0.017) compared to those with CC genotype. A meta-analysis revealed that the frequency of carrier's genotypes was significantly higher in PD than in control subjects (OR = 1.31, 95% CI = 1.19, 1.44, P < 0.00001). The gender, age of onset, Hoehn–Yahr stage and UPDRS scores and clinical features were similar between carriers and non-carriers. In conclusion, we demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of PD in Han Chinese patients from mainland China and the meta-analysis with European populations revealed a similar finding. However, carriers cannot be distinguished from non-carriers based on their clinical features or motor severity. Functional studies of GAK to unravel its role in the pathophysiologic pathway of PD will be useful.

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References

  • Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U, Mountain JL, Goldman SM, Tanner CM, Langston JW (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genetics 7(6):e1002141. doi:10.1371/journal.pgen.1002141

  • Dumitriu A, Pacheco CD, Wilk JB, Strathearn KE, Latourelle JC, Goldwurm S, Pezzoli G, Rochet JC, Lindquist S, Myers RH (2011) Cyclin-G-associated kinase modifies α-synuclein expression levels and toxicity in Parkinson’s disease: results from the GenePD Study. Hum Mol Genet 20(8):1478–1487. doi:10.1093/hmg/ddr026

    Article  PubMed  CAS  Google Scholar 

  • Fung HC, Scholz S, Matarin M, Simón-Sánchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J (2006) Genome-wide genotyping in Parkinson’s disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5 (11):911–916. doi:10.1016/S1474-4422(06)70578-6

    Google Scholar 

  • Grünblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 111(12):1543–1573. doi:10.1007/s00702-004-0212-1

    Article  PubMed  Google Scholar 

  • Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42(9):781–785. doi:10.1038/ng.642

    Article  PubMed  CAS  Google Scholar 

  • Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184

    Article  PubMed  CAS  Google Scholar 

  • Kimura SH, Tsuruga H, Yabuta N, Endo Y, Nojima H (1997) Structure, expression, and chromosomal localization of human GAK. Genomics 44(2):179–187. doi:10.1006/geno.1997.4873

    Article  PubMed  CAS  Google Scholar 

  • Latourelle JC, Pankratz N, Dumitriu A, Wilk JB, Goldwurm S, Pezzoli G, Mariani CB, DeStefano AL, Halter C, Gusella JF, Nichols WC, Myers RH, Foroud T (2009) Genomewide association study for onset age in Parkinson disease. BMC Med Genet 10:98. doi:10.1186/1471-2350-10-98

    Article  PubMed  Google Scholar 

  • Liu X, Cheng R, Verbitsky M, Kisselev S, Browne A, Mejia-Santana H, Louis E, Cote L, Andrews H, Waters C (2011) Genome-wide association study identifies candidate genes for Parkinson’s disease in an Ashkenazi Jewish population. BMC medical genetics 12(1):104. doi:10.1186/1471-2350-12-104

  • Maraganore DM, De Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, Pant P, Frazer KA, Cox DR, Ballinger DG (2005) High-resolution whole-genome association study of Parkinson disease. Am J Hum Genetics 77(5):685–693. doi:10.1086/496902

    Article  CAS  Google Scholar 

  • Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, Doheny KF, Gusella JF, Nichols WC, Foroud T (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124(6):593–605. doi:10.1007/s00439-008-0582-9

    Article  PubMed  CAS  Google Scholar 

  • Rhodes SL, Sinsheimer JS, Bordelon Y, Bronstein JM, Ritz B (2011) Replication of GWAS associations for GAK and MAPT in Parkinson’s disease. Ann Hum Genet 75(2):195–200. doi:10.1111/j.1469-1809.2010.00616.x

    PubMed  CAS  Google Scholar 

  • Saad M, Lesage S, Saint-Pierre A, Corvol JC, Zelenika D, Lambert JC, Vidailhet M, Mellick GD, Lohmann E, Durif F (2011) 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 20(3):615–627. doi:10.1093/hmg/ddq497

    Article  PubMed  Google Scholar 

  • Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 41(12):1303–1307. doi:10.1038/ng.485

    Article  PubMed  CAS  Google Scholar 

  • Sato J, Shimizu H, Kasama T, Yabuta N, Nojima H (2009) GAK, a regulator of clathrin-mediated membrane trafficking, localizes not only in the cytoplasm but also in the nucleus. Genes to Cells 14(5):627–641. doi:10.1111/j.1365-2443.2009.01296.x

    Article  PubMed  CAS  Google Scholar 

  • Shimizu H, Nagamori I, Yabuta N, Nojima H (2009) GAK, a regulator of clathrin-mediated membrane traffic, also controls centrosome integrity and chromosome congression. J Cell Sci 122(17):3145–3152. doi:10.1242/jcs.052795

    Article  PubMed  CAS  Google Scholar 

  • Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41(12):1308–1312. doi:10.1038/ng.487

    Article  PubMed  CAS  Google Scholar 

  • Simón-Sánchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, Arepalli S, Hernandez DG, de Bie RM, Velseboer D, Scheffer H, Bloem B, van Dijk KD, Rivadeneira F, Hofman A, Uitterlinden AG, Rizzu P, Bochdanovits Z, Singleton AB, Heutink P (2011) Genome-wide association study confirms extant PD risk loci among the Dutch. Eur J Hum Genet 19(6):655–661. doi:10.1038/ejhg.2010.254

    Article  PubMed  Google Scholar 

  • Spencer CC, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G, Barker RA, Bellenguez C, Bhatia K, Blackburn H, Blackwell JM, Bramon E, Brown MA, Burn D, Casas JP, Chinnery PF, Clarke CE, Corvin A, Craddock N, Deloukas P, Edkins S, Evans J, Freeman C, Gray E, Hardy J, Hudson G, Hunt S, Jankowski J, Langford C, Lees AJ, Markus HS, Mathew CG, McCarthy MI, Morrison KE, Palmer CN, Pearson JP, Peltonen L, Pirinen M, Plomin R, Potter S, Rautanen A, Sawcer SJ, Su Z, Trembath RC, Viswanathan AC, Williams NW, Morris HR, Donnelly P, Wood NW (2011) Dissection of the genetics of Parkinson’s disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet 20(2):345–353. doi:10.1093/hmg/ddq469

    Article  PubMed  CAS  Google Scholar 

  • Tan EK, Schapira AH (2011) LRRK2 as a therapeutic target in Parkinson’s disease. Eur J Neurol 18(4):545–546. doi:10.1111/j.1468-1331.2010.03305.x

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The study was supported by Duke–NUS Graduate Medical School, Singapore Millennium Foundation, and the National Natural Science Foundation of China (No: 30870846). We gratefully acknowledge Professor Dong Zhou, Li He, Guanggu Yuan and Yingru Gou. We would also like to thank Dr. Wenjun Chen, Yan Wu, Xingkai An, Zijuan Zhang and all staff in the laboratory for their help.

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Authors and Affiliations

  1. Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Nan-Nan Li, Xue-Li Chang, Xue-Ye Mao, Dong-Mei Zhao & Rong Peng

  2. Department of Internal Medicine, Wangjiang Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Jin-Hong Zhang

  3. Department of Neurology, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore

    Eng-King Tan

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  1. Nan-Nan Li
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  2. Xue-Li Chang
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  4. Jin-Hong Zhang
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  5. Dong-Mei Zhao
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  7. Rong Peng
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Correspondence to Rong Peng.

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Li, NN., Chang, XL., Mao, XY. et al. GWAS-linked GAK locus in Parkinson’s disease in Han Chinese and meta-analysis. Hum Genet 131, 1089–1093 (2012). https://doi.org/10.1007/s00439-011-1133-3

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  • DOI: https://doi.org/10.1007/s00439-011-1133-3

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