Neurological Sciences

, Volume 35, Issue 10, pp 1495–1504

The association between the LRRK2 G2385R variant and the risk of Parkinson’s disease: a meta-analysis based on 23 case–control studies

  • Cheng-long Xie
  • Jia-Lin Pan
  • Wen-Wen Wang
  • Yu Zhang
  • Su-fang Zhang
  • Jing Gan
  • Zhen-Guo Liu
Review Article

Abstract

Clinical diagnosis of Parkinson’s disease (PD) is essential but misdiagnosis of PD-like diseases is quite common. LRRK2 G2385R variants have been extensively examined for the association to the risk of Parkinson’s disease. However, results from different studies are inconsistent. The purpose of this meta-analysis was to assess the association between the LRRK2 G2385R variants and the risk of PD. A systematic literature search was performed for 6 databases up to January of 2014 to identify case–control studies involving LRRK2 G2385R variants and the risk of PD. A total of 12,915 cases and 12,451 controls in 23 case–control studies were included in this meta-analysis. The results indicated that the variant A allele carriers (GA + AA) increased risk of PD when compared with the homozygote GG (GA + AA vs. GG: OR = 2.4, 95 % CI = 1.97 to 2.92, P < 0.00001). In the subgroup analysis by ethnicity, increased risks were identified among Chinese (OR = 2.69, 95 % CI = 2.1–3.45, P < 0.00001) as well as in non-Chinese (OR = 2.17, 95 % CI 1.75–2.69, P < 0.00001). In the subgroup analysis by age of onset, significant associations were found in both later-onset PD (LOPD) and early-onset PD (EOPD) cases. And there was no significant difference of the allele frequency between patients with LOPD and EOPD (OR = 1.18, 95 % CI = 0.77–1.80, P = 0.45). Our results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD. Meanwhile, it is possible that age is not the risk factor to facilitate G2385R gene mutation.

Keywords

Parkinson’s disease LRRK2 G2385R Polymorphism Meta-analysis 

References

  1. 1.
    Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Pathological α-synuclein transmission initiates Parkinson like neurodegeneration in nontransgenic mice. Science 338:949–953PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ (2002) The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125:861–870PubMedCrossRefGoogle Scholar
  3. 3.
    Martí MJ, Tolosa E (2013) Parkinson disease: New guidelines for diagnosis of Parkinson disease. Nat Rev Neurol 9:190–191PubMedCrossRefGoogle Scholar
  4. 4.
    Gan-Or Z, Ozelius LJ, Bar-Shira A, Saunders-Pullman R, Mirelman A, Kornreich R, Gana-Weisz M, Raymond D, Rozenkrantz L, Deik A, Gurevich T, Gross SJ, Schreiber-Agus N, Giladi N, Bressman SB, Orr-Urtreger A (2013) The p. L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 80:1606–1610PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    McInerney-Leo A (2005) Genetic testing in Parkinson’s disease. Mov Disord 20:908–909PubMedCrossRefGoogle Scholar
  6. 6.
    Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68:201–206PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kett LR, Boassa D, Ho CC, Rideout HJ, Hu J, Terada M, Ellisman M, Dauer WT (2012) LRRK2 Parkinson disease mutations enhance its microtubule association. Hum Mol Genet 21:890–899PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600PubMedCrossRefGoogle Scholar
  9. 9.
    Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilariño-Güell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ (2011) Genetic Epidemiology Of Parkinson’s Disease (GEO-PD) Consortium. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case-control study. Lancet Neurol 10:898–908PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Dächsel JC, Farrer MJ (2010) LRRK2 and Parkinson disease. Arch Neurol 67:542–547PubMedCrossRefGoogle Scholar
  11. 11.
    Paisán-Ruiz C (2009) LRRK2 gene variation and its contribution to Parkinson disease. Hum Mutat 30:1153–1160PubMedCrossRefGoogle Scholar
  12. 12.
    Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM (2008) Analysis of Lrrk2 R1628P as a risk factor for Parkinson’s disease. Ann Neurol 64:88–92PubMedCrossRefGoogle Scholar
  13. 13.
    An XK, Peng R, Li T, Burgunder JM, Wu Y, Chen WJ, Zhang JH, Wang YC, Xu YM, Gou YR, Yuan GG, Zhang ZJ (2008) LRRK2 Gly2385Arg variant is a risk factor of Parkinson’s disease among Han-Chinese from mainland China. Eur J Neurol 15:301–305PubMedCrossRefGoogle Scholar
  14. 14.
    Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ (2007) The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence. Hum Genet 120:857–863PubMedCrossRefGoogle Scholar
  15. 15.
    Tan EK, Peng R, Wu YR, Wu RM, Wu-Chou YH, Tan LC, An XK, Chen CM, Fook-Chong S, Lu CS (2009) LRRK2 G2385R modulates age at onset in Parkinson’s disease: a multi-center pooled analysis. Am J Med Genet B Neuropsychiatr Genet 150:1022–1023CrossRefGoogle Scholar
  16. 16.
    Li Y, Tang K, Zhang Z, Zhang M, Zeng Z, He Z, He L, Wan C (2011) Genetic diversity of the apolipoprotein E gene and diabetic nephropathy: a meta analysis. Mol Biol Rep 38:3243–3252PubMedCrossRefGoogle Scholar
  17. 17.
    Fung HC, Chen CM, Hardy J, Singleton AB, Wu YR (2006) A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan. BMC Neurol 6:47–50PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohé CF, Chang HC, Chen RS, Weng YH, Vanacore N, Breedveld GJ, Oostra BA, Bonifati V (2006) A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics 7:133–138PubMedCrossRefGoogle Scholar
  19. 19.
    Tan EK, Zhao Y, Tan L, Lim HQ, Lee J, Yuen Y, Pavanni R, Wong MC, Fook-Chong S, Liu JJ (2007) Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians. Mov Disord 22:1816–1818PubMedCrossRefGoogle Scholar
  20. 20.
    Funayama M, Li Y, Tomiyama H, Yoshino H, Imamichi Y, Yamamoto M, Murata M, Toda T, Mizuno Y, Hattori N (2007) Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. NeuroReport 18:273–275PubMedCrossRefGoogle Scholar
  21. 21.
    Farrer MJ, Stone JT, Lin CH, Dächsel JC, Hulihan MM, Haugarvoll K, Ross OA, Wu RM (2007) Lrrk2 G2385R is an ancestral risk factor for Parkinson’s disease in Asia. Parkinsonism Relat Disord 13:89–92PubMedCrossRefGoogle Scholar
  22. 22.
    Li C, Ting Z, Qin X, Ying W, Li B, Guo Qiang L, Jian Fang M, Jing Z, Jian Qing D, Di Sheng C (2007) The prevalence of LRRK2 Gly2385Arg variant in Chinese Han population with Parkinson’s disease. Mov Disord 22:2439–2443PubMedCrossRefGoogle Scholar
  23. 23.
    Choi JM, Woo MS, Ma HI, Kang SY, Sung YH, Yong SW, Chung SJ, Kim JS, Shin HW, Lyoo CH, Lee PH, Baik JS, Kim SJ, Park MY, Sohn YH, Kim JH, Kim JW, Lee MS, Lee MC, Kim DH, Kim YJ (2008) Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics 9:263–269PubMedCrossRefGoogle Scholar
  24. 24.
    Zabetian CP, Yamamoto M, Lopez AN, Ujike H, Mata IF, Izumi Y, Kaji R, Maruyama H, Morino H, Oda M, Hutter CM, Edwards KL, Schellenberg GD, Tsuang DW, Yearout D, Larson EB, Kawakami H (2009) LRRK2 mutations and risk variants in Japanese patients with Parkinson’s disease. Mov Disord 24:1034–1041PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Pulkes T, Papsing C, Mahasirimongkol S, Busabaratana M, Kulkantrakorn K, Tiamkao S (2011) Frequencies of LRRK2 variants in Thai patients with Parkinson’s disease: evidence for an R1628P founder. J Neurol Neurosurg Psychiatry 82:1179–1180PubMedCrossRefGoogle Scholar
  26. 26.
    Miyake Y, Tsuboi Y, Koyanagi M, Fujimoto T, Shirasawa S, Kiyohara C, Tanaka K, Fukushima W, Sasaki S, Yamada T, Oeda T, Miki T, Kawamura N, Sakae N, Fukuyama H, Hirota Y, Nagai M, Kinki F (2010) LRRK2 Gly2385Arg polymorphism, cigarette smoking, and risk of sporadic Parkinson’s disease: a case-control study in Japan. J Neurol Sci 297:15–18PubMedCrossRefGoogle Scholar
  27. 27.
    Tan EK, Peng R, Teo YY, Tan LC, Angeles D, Ho P, Chen ML, Lin CH, Mao XY, Chang XL, Prakash KM, Liu JJ, Au WL, Le WD, Jankovic J, Burgunder JM, Zhao Y, Wu RM (2010) Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study. Hum Mutat 31:561–568PubMedGoogle Scholar
  28. 28.
    Kim JM, Lee JY, Kim HJ, Kim JS, Shin ES, Cho JH, Park SS, Jeon BS (2010) The LRRK2 G2385R variant is a risk factor for sporadic Parkinson’s disease in the Korean Population. Parkinsonism Relat Disord 16:85–88PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou Y, Luo X, Li F, Tian X, Zhu L, Yang Y, Ren Y, Pang H (2012) Association of Parkinson’s disease with six single nucleotide polymorphisms located in four PARK genes in the northern Han Chinese population. J Clin Neurosci 19:1011–1015PubMedCrossRefGoogle Scholar
  30. 30.
    Yan H, Ma Q, Yang X, Wang Y, Yao Y, Li H (2012) Correlation between LRRK2 gene G2385R polymorphisms and Parkinson’s disease. Mol Med Rep 6:879–883PubMedGoogle Scholar
  31. 31.
    Sadhukhan T, Vishal M, Das G, Sharma A, Mukhopadhyay A, Das SK, Ray K, Ray J (2012) Evaluation of the role of LRRK2 gene in Parkinson’s disease in an East Indian Cohort. Dis Markers 32:355–362PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Wang C, Cai Y, Zheng Z, Tang BS, Xu Y, Wang T, Ma J, Chen SD, Langston JW, Tanner CM, Chan P (2012) Chinese Parkinson Study Group (CPSG), Penetrance of LRRK2 G2385R and R1628P is modified by common PD-associated genetic variants. Parkinsonism Relat Disord 18:958–963PubMedCrossRefGoogle Scholar
  33. 33.
    Cai J, Lin Y, Chen W, Lin Q, Cai B, Wang N, Zheng W (2013) Association between G2385R and R1628P polymorphism of LRRK2 gene and sporadic Parkinson’s disease in a Han-Chinese population in south-eastern China. Neurol Sci Apr 30Google Scholar
  34. 34.
    Wu-Chou YH, Chen YT, Yeh TH, Chang HC, Weng YH, Lai SC, Huang CL, Chen RS, Huang YZ, Chen CC, Hung J, Chuang WL, Lin WY, Chen CH, Lu CS (2013) Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: a replication study in a Taiwanese cohort. Parkinsonism Relat Disord 19:251–255PubMedCrossRefGoogle Scholar
  35. 35.
    Fu X, Zheng Y, Hong H, He Y, Zhou S, Guo C, Liu Y, Xian W, Zeng J, Li J, Liu Z, Chen L, Pei Z (2013) LRRK2 G2385R and LRRK2 R1628P increase risk of Parkinson’s disease in a Han Chinese population from Southern Mainland China. Parkinsonism Relat Disord 19:397–398PubMedCrossRefGoogle Scholar
  36. 36.
    Lin BF, Zheng CH, Wang XJ, Cheng HP (2013) Association between G2385R polymorphisms of LRRK2 gene and Parkinson`s disease. Zhejiang Medical J 13:881–884Google Scholar
  37. 37.
    Muangpaisan W, Hori H, Brayne C (2009) Systematic review of the prevalence andincidence of Parkinson’s disease in Asia. J Epidemiol 19:281–293PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s Disease. Neuron 44:595–600PubMedCrossRefGoogle Scholar
  39. 39.
    Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A (2006) French Parkinson’s Disease Genetics Study Group. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Engl J Med 354:422–423PubMedCrossRefGoogle Scholar
  40. 40.
    Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L (2006) LRRK2 expression linked to dopamine-innervated areas. Ann Neurol 59:714–719PubMedCrossRefGoogle Scholar
  41. 41.
    Rideout HJ, Stefanis L (2014) The neurobiology of LRRK2 and its role in the pathogenesis of Parkinson’s disease. Neurochem Res 39:576–592PubMedCrossRefGoogle Scholar
  42. 42.
    Rudenko IN, Kaganovich A, Hauser DN, Beylina A, Chia R, Ding J, Maric D, Jaffe H, Cookson MR (2012) The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson’s disease is a partial loss-of-function mutation. Biochem J 446:99–111PubMedCrossRefGoogle Scholar
  43. 43.
    Peeraully T, Tan EK (2012) Genetic variants in sporadic Parkinson’s disease: east vs West. Parkinsonism Relat Disord 18(Suppl 1):S63–S65PubMedCrossRefGoogle Scholar
  44. 44.
    Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105:1048–1056PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Ruffmann C, Giaccone G, Canesi M, Bramerio M, Goldwurm S, Gambacorta M, Rossi G, Tagliavini F, Pezzoli G (2012) Atypical tauopathy in a patient with LRRK2-G2019S mutation and tremor-dominant Parkinsonism. Neuropathol Appl Neurobiol 38:382–386PubMedCrossRefGoogle Scholar
  46. 46.
    Ujiie S, Hatano T, Kubo S, Imai S, Sato S, Uchihara T, Yagishita S, Hasegawa K, Kowa H, Sakai F, Hattori N (2012) LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat Disord 18:819–823PubMedCrossRefGoogle Scholar
  47. 47.
    Wider C, Dickson DW, Wszolek ZK (2010) Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegener Dis 7:175–179PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, Alonso-Coello P, Djulbegovic B, Atkins D, Falck-Ytter Y, Williams JW Jr, Meerpohl J, Norris SL, Akl EA, Schünemann HJ (2011) GRADE guidelines: 5. Rating the quality of evidence–publication bias. J Clin Epidemiol 64:1277–1282PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  • Cheng-long Xie
    • 1
  • Jia-Lin Pan
    • 2
  • Wen-Wen Wang
    • 3
  • Yu Zhang
    • 1
  • Su-fang Zhang
    • 1
  • Jing Gan
    • 1
  • Zhen-Guo Liu
    • 1
  1. 1.Department of NeurologyXinhua Hospital, Affiliated to Shanghai Jiaotong University School of MedicineShanghaiPeople’s Republic of China
  2. 2.Department of CardiologyThe Second Affiliated Hospital of Wenzhou Medical UniversityWenzhouPeople’s Republic of China
  3. 3.The Center of Traditional Chinese Medicine, the Second Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina

Personalised recommendations