Skip to main content

Association between 5-HTTLPR polymorphism and Parkinson’s disease: a meta analysis

Abstract

To investigate the genetic association of 5-HTTLPR polymorphism and Parkinson’s disease (PD) or depression in PD by using meta analysis. Published association studies on genotype or allele frequencies of the 5-HTTLPR in patients with or without PD or in PD patients with or without depression in all ethnic groups were included. A biallelic meta-analysis, including biallelic frequency model, biallelic dominant model (BDM) and biallelic recessive model, was performed using the Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio and its corresponding 95 % CI with a random-effect model. Six studies met the criteria for the meta-analysis of association of 5-HTTLPR and three studies were included for the association of 5-HTTLPR and depression in PD. The meta-analysis results did not show significant association between 5-HTTLPR and PD or depression in PD, except for a moderate negative association between 5-HTTLPR and PD in Asian subgroup (2 studies) using the BDM approach. Our meta-analysis result does not support a direct primary effect of 5-HTTLPR on PD or depression in PD. Further association studies with larger sample sizes preferably taking into consideration factors such as additional allelic variants in the 5-HTTLPR, ethnic variation of the 5-HTTLPR distribution and gene–gene interaction are necessary to reach a more definite conclusion.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Benitez BA, Forero DA, Arboleda GH, Granados LA, Yunis JJ, Fernandez W et al (2010) Exploration of genetic susceptibility factors for Parkinson’s disease in a South American sample. J Genet 89:229–232

    Article  PubMed  Google Scholar 

  2. Mössner R, Henneberg A, Schmitt A, Syagailo YV, Grässle M, Hennig T et al (2001) Allelic variation of serotonin transporter expression is associated with depression in Parkinson’s disease. Mol Psychiatry 6:350–352

    Article  PubMed  Google Scholar 

  3. Belin AC, Westerlund M (2008) Parkinson’s disease: a genetic perspective. FEBS J 275:1377–1383

    CAS  Article  PubMed  Google Scholar 

  4. Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Gwinn-Hardy K, Singleton A (2006) Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 60:389–398

    CAS  Article  PubMed  Google Scholar 

  5. Kish SJ, Tong J, Hornykiewicz O, Rajput A, Chang LJ, Guttman M et al (2008) Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain 131:120–131

    PubMed  Google Scholar 

  6. Guttman M, Boileau I, Warsh J, Saint-Cyr JA, Ginovart N, McCluskey T et al (2007) Brain serotonin transporter binding in non-depressed patients with Parkinson’s disease. Eur J Neurol 14:523–528

    CAS  Article  PubMed  Google Scholar 

  7. Zhang X, Andren PE, Greengard P, Svenningsson P (2008) Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of parkinsonism. Proc Natl Acad Sci USA 105:2163–2168

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. Kish SJ (2003) Biochemistry of Parkinson’s disease: is a brain serotonergic deficiency a characteristic of idiopathic Parkinson’s disease? Adv Neurol 91:39–49

    CAS  PubMed  Google Scholar 

  9. Fukunishi I, Hosokawa K, Ozaki S (1991) Depression antedating the onset of Parkinson’s disease. Jpn J Psychiatry Neurol 45:7–11

    CAS  PubMed  Google Scholar 

  10. Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T et al (1997) Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 2:457–462

    CAS  Article  PubMed  Google Scholar 

  11. Kunugi H, Tatsumi M, Sakai T, Hattori M, Nanko S, Stober G et al (1996) Serotonin transporter gene polymorphism and affective disorder. Lancet 347:1340

    CAS  Article  PubMed  Google Scholar 

  12. Murphy DL, Lerner A, Rudnick G, Lesch KP (2004) Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 4:109–123

    CAS  Article  PubMed  Google Scholar 

  13. Maeda T, Nagata K, Yoshida Y, Kannari K (2005) Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered L-DOPA. Brain Res 1046:230–233

    CAS  Article  PubMed  Google Scholar 

  14. Kannari K, Shen H, Arai A, Tomiyama M, Baba M (2006) Reuptake of L-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters. Neurosci Lett 402:62–65

    CAS  Article  PubMed  Google Scholar 

  15. Burn DJ (2002) Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson’s disease. Mov Disord 17:445–454

    Article  PubMed  Google Scholar 

  16. Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T et al (1997) Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 2:457–462

    CAS  Article  PubMed  Google Scholar 

  17. Menza M (2006) STAR*D: the results begin to roll in. Am J Psychiatry 163:1123

    Article  PubMed  Google Scholar 

  18. Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5:32–38

    CAS  Article  PubMed  Google Scholar 

  19. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    CAS  Article  PubMed  Google Scholar 

  20. Li D, He L (2007) Meta-analysis supports association between serotonin transport (5-HTT) and suicidal behavior. Mol Psychiatry 12:47–54

    Article  PubMed  Google Scholar 

  21. Albani D, Vittori A, Batelli S, Polito L, De Mauro S, Galimberti D et al (2009) Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson’s disease in Italy. Eur Neurol 62:120–123

    CAS  Article  PubMed  Google Scholar 

  22. Menza MA, Palermo B, DiPaola R, Sage JI, Ricketts MH (1999) Depression and anxiety in Parkinson’s disease: possible effect of genetic variation in the serotonin transporter. J Geriatr Psychiatry Neurol 12:49–52

    CAS  Article  PubMed  Google Scholar 

  23. Zhang J-L, Yang J-F, Chan P (2009) No association between polymorphism of serotonin transporter gene and depression in Parkinson’s disease in Chinese. Neurosci Lett 455:155–158

    CAS  Article  PubMed  Google Scholar 

  24. Burn DJ, Tiangyou W, Allcock LM, Davison J, Chinnery PF (2006) Allelic variation of a functional polymorphism in the serotonin transporter gene and depression in Parkinson’s disease. Parkinsonism Relat Disord 12:139–141

    Article  PubMed  Google Scholar 

  25. Dissanayaka NN, Silburn PA, O’Sullivan JD, Mellick GD (2009) Serotonin and dopamine transporter genes do not influence depression in Parkinson’s disease. Mov Disord 24:111–115

    Article  PubMed  Google Scholar 

  26. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M et al. (2004) The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analysis. Ottawa Health Research Institute, Ottawa

  27. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    CAS  Article  PubMed  Google Scholar 

  28. Higgins J, Thompson S, Deeks J, Altman D (2002) Statistical heterogeneity in systematic reviews of clincial trials: a critical appraisal of guidelines and practice. J Health Serv Res Policy 7:51–61

    Article  PubMed  Google Scholar 

  29. Navarro-Mateu F, Escámez T, Koenen KC, Alonso J, Sánchez-Meca J (2013) Meta-analyses of the 5-HTTLPR polymorphism and post-traumatic stress disorder. PLoS ONE 8:e66227

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  30. Paus S, Seeger G, Brecht HM, Köster J, El-Faddagh M, Nöthen MM et al (2004) Association study of dopamine D2, D3, D4 receptor and serotonin transporter gene polymorphism with sleep attacks in Parkinson’s disease. Mov Disord 19:705–707

    Article  PubMed  Google Scholar 

  31. McCann SJ, McManus ME, Johnson AG, Mellick GD, Le Couteur DG, Pond SM (2000) The serotonin transporter gene and Parkinson’s disease. Eur Neurol 44:108–111

    CAS  Article  PubMed  Google Scholar 

  32. Güzey C, Allard P, Brännström T, Spigset O (2012) Radioligand binding to brain dopamine and serotonin receptors and transporters in Parkinson’s disease: relation to gene polymorphisms. Int J Neurosci 122:124–132

    Article  PubMed  Google Scholar 

  33. Mössner R, Schmitt A, Syagailo Y, Gerlach M, Riederer P, Lesch KP (2000) The serotonin transporter in Alzheimer’s and Parkinson’s disease. J Neural Transm 60:345–350

    Google Scholar 

  34. Cormier F, Muellner J, Corvol JC (2013) Genetics of impulse control in Parkinson’s disease. J Neural Transm 120:665–671

    CAS  Article  PubMed  Google Scholar 

  35. Mössner R, Riederer P (2007) Allelic variation of a functional promoter polymorphism of the serotonin transporter and depression in Parkinson’s disease. Parkinsonism Relat Disord 13:62

    Article  PubMed  Google Scholar 

  36. Kiferle L, Petrozzi L, Rossi C et al (2006) Psychiatric disorders in Parkinson’s disease: role of 5-HTTLPR and 5-HT2A polymorphisms. Eur J Neurol 13:220

    Article  Google Scholar 

  37. Rocchi A, Kiferle L, Petrozzia L, Frosini D, Siciliano G, Bonuccelli U et al (2005) Serotoninergic polymorphism (5-HTTLPR and 5-HT2A): association studies with neuropsychiatric disturbances in Parkinson’s disease. Clin Chem Acta 355:172

    Google Scholar 

  38. Tiangyou W, Pyle A, Keers SM, Allcock LM, Davison J, Burn DJ et al (2006) The role of serotonin transporter gene polymorphisms in depression in Parkinson’s disease. Mov Disord 21:S661–S661

    Google Scholar 

  39. Goldman JG, Goetz CG, Berry-Kravis E, Leurgans SE, Zhou L, Desai C (2004) Serotonin transporter gene polymorphisms and hallucinations in Parkinson’s disease. Ann Neurol 56:S26–S26

    Google Scholar 

  40. Ricketts MH, Hamer RM, Sage JI, Manowitz P, Feng F, Menza MA (1998) Association of a serotonin transporter gene promoter polymorphism with harm avoidance behavior in an elderly population. Psychiatr Genet 8:41–44

    CAS  Article  PubMed  Google Scholar 

  41. Kiferle L, Ceravolo R, Petrozzi L (2007) Visual hallucinations in Parkinson’s disease are not influenced by polymorphisms of serotonin 5-HT2A receptor and transporter gene. Neurosci Lett 422:228–231

    CAS  Article  PubMed  Google Scholar 

  42. Lee JY, Lee EK, Park SS, Lim JY, Kim HJ, Kim JS et al (2009) Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson’s disease. Mov Disord 24:1803–1810

    Article  PubMed  Google Scholar 

  43. Lee JY, Cho J, Lee EK, Park SS, Jeon BS (2011) Differential genetic susceptibility in diphasic and peak-dose dyskinesias in Parkinson’s disease. Mov Disord 26:73–79

    Article  PubMed  Google Scholar 

  44. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29:8–16

    CAS  Article  PubMed  Google Scholar 

  45. Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) showed ten novel allelic variants. Mol Psychiatry 5:32–38

    CAS  Article  PubMed  Google Scholar 

  46. Zalsman G, Huang YY, Oquendo MA, Burke AK, Hu XZ, Brent DA et al (2006) Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. Am J Psychiatry 163:1588–1593

    Article  PubMed  Google Scholar 

  47. Parsey RV, Hastings RS, Oquendo MA, Hu X, Goldman D, Huang YY et al (2006) Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163:48–51

    Article  PubMed  Google Scholar 

  48. Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–752

    CAS  PubMed  Google Scholar 

  49. Vinkhuyzen AA, Dumenil T, Ryan L, Gordon SD, Henders AK, Madden PA et al (2011) Identification of tag haplotypes for 5HTTLPR for different genome-wide SNP platforms. Mol Psychiatry 16:1073–1075

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  50. Haenisch B, Herms S, Mattheisen M, Steffens M, Breuer R, Strohmaier J et al (2013) Genome-wide association data provide further support for an association between 5-HTTLPR and major depressive disorder. J Affect Disord 146:438–440

    CAS  Article  PubMed  Google Scholar 

  51. Sagoo GS, Little J, Higgins JP (2009) Systematic reviews of genetic association studies. Human genome epidemiology network. PLoS Med 6:e1000028

    PubMed Central  Article  Google Scholar 

  52. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genet Med 4:45–61

    CAS  Article  PubMed  Google Scholar 

  53. M, Higgins J, Ioannidis JBray , Khourys M, Little J, Manolio T et al. (2006) The HuGENetTm HUGE review handbook. version 1.0

  54. PDGene, a database for Parkinson’s disease genetic association studies developed by the Max Planck Institute for Molecular Genetics Berlin, the Michael. J. Fox Foundation and the Alzheimer Research Forum. http://www.pdgene.org/meta.asp?geneID=90. Accessed 12 Jan 2013

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Lianbo Gao.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gao, L., Gao, H. Association between 5-HTTLPR polymorphism and Parkinson’s disease: a meta analysis. Mol Biol Rep 41, 6071–6082 (2014). https://doi.org/10.1007/s11033-014-3484-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3484-z

Keywords

  • 5-HTTLPR
  • Parkinson’s disease
  • Depression
  • Meta-analysis