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Molecular genetics of obsessive–compulsive disorder: a comprehensive meta-analysis of genetic association studies

Molecular Psychiatry volume 18, pages 799–805 (2013)Cite this article

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Abstract

Twin studies indicate that obsessive–compulsive disorder (OCD) is strongly influenced by additive genetic factors. Yet, molecular genetic association studies have yielded inconsistent results, possibly because of differences across studies in statistical power. Meta-analysis can yield greater power. This study reports the first comprehensive meta-analysis of the relationship between OCD and all previously examined polymorphisms for which there was sufficient information in the source studies to compute odds ratios (ORs). A total of 230 polymorphisms from 113 genetic association studies were identified. A full meta-analysis was conducted for 20 polymorphisms that were examined in 5 or more data sets, and a secondary meta-analysis (limited to the computation of mean effect sizes) was conducted for 210 polymorphisms that were examined in fewer than 5 data sets. In the main meta-analysis, OCD was associated with serotonin-related polymorphisms (5-HTTLPR and HTR2A) and, in males only, with polymorphisms involved in catecholamine modulation (COMT and MAOA). Nonsignificant trends were identified for two dopamine-related polymorphisms (DAT1 and DRD3) and a glutamate-related polymorphism (rs3087879). The secondary meta-analysis identified another 18 polymorphisms with significant ORs that merit further investigation. This study demonstrates that OCD is associated with multiple genes, with most having a modest association with OCD. This suggests a polygenic model of OCD, consistent with twin studies, in which multiple genes make small, incremental contributions to the risk of developing the disorder. Future studies, with sufficient power to detect small effects, are needed to investigate the genetic basis of OCD subtypes, such as early vs late onset OCD.

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References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,, 4th edn, text rev edn. Author: Washington, DC, 2000.

  2. Taylor S, Jang KL, Asmundson GJG . Etiology of obsessions and compulsions: a behavioral-genetic analysis. J Abnorm Psychol 2010; 119: 672–682.

    Article  Google Scholar 

  3. Taylor S . Etiology of obsessions and compulsions: a meta-analysis and narrative review of twin studies. Clin Psychol Rev 2011; 31: 1361–1372.

    Article  Google Scholar 

  4. Plomin R, Defries JC, Craig IW, McGuffin P . Behavioral Genetics in the Postgenomic Era. American Psychological Association: Washington, DC, 2002.

    Google Scholar 

  5. Abramowitz JS, Taylor S, McKay D . Obsessive-compulsive disorder. Lancet 2009; 374: 491–499.

    Article  Google Scholar 

  6. Pauls DL . The genetics of obsessive-compulsive disorder: a review. Dialogues Clin Neurosci 2010; 12: 149–163.

    PubMed  PubMed Central  Google Scholar 

  7. Borenstein M, Hedges LV, Higgins J, Rothstein H . Introduction to Meta-Analysis. Wiley: Chichester, 2009.

    Book  Google Scholar 

  8. Taylor S . Early versus late onset obsessive-compulsive disorder: evidence for distinct subtypes. Clin Psychol Rev 2011; 31: 1083–1100.

    Article  Google Scholar 

  9. Azzam A, Mathews CA . Meta-analysis of the association between the catecholamine-O-methyl-transferase gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2003; 123: 64–69.

    Article  Google Scholar 

  10. Pooley EC, Fineberg N, Harrison PJ . The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and meta-analysis. Mol Psychiatry 2007; 12: 556–561.

    Article  CAS  Google Scholar 

  11. Schaid DJ . Transmission disequilibrium, family controls, and great expectations. Am J Hum Genet 1998; 63: 935–941.

    Article  CAS  Google Scholar 

  12. Lewis CM . Genetic association studies: design, analysis and interpretation. Brief Bioinform 2002; 3: 146–153.

    Article  CAS  Google Scholar 

  13. Lin PY . Meta-analysis of the association of serotonin transporter gene polymorphism with obsessive–compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 683–689.

    Article  CAS  Google Scholar 

  14. Bloch MH, Landeros-Weisenberger A, Sen S, Dombrowski P, Kelmendi B, Corci V et al. Association of the serotonin transporter polymorphism and obsessive-compulsive disorder: systematic review. Am J Med Genet B Neuropsychiatr Genet 2008; 147: 850–858.

    Article  Google Scholar 

  15. Voyiaziakis E, Evgrafov O, Li D, Yoon HJ, Tabares P, Samuels J et al. Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study. Mol Psychiatry 2011; 16: 108–120.

    Article  CAS  Google Scholar 

  16. Wendland JR KM, Cromer KR, Murphy DL . A large case-control study of common functional SLC6A4 and BDNF variants in obsessive-compulsive disorder. Neuropsychopharmacology 2007; 32: 2543–2551.

    Article  CAS  Google Scholar 

  17. Lefebvre C, Manheimer E, Glanville J . Searching for studies. In: Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions. Wiley: New York, 2008 pp 146–153.

    Google Scholar 

  18. Borenstein M, Hedges LV, Higgins J, Rothstein H . Comprehensive Meta-Analysis, 2.2050 edn. Biostat: Englewood, NJ, 2009.

    Google Scholar 

  19. Perneger TV . What′s wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–1238.

    Article  CAS  Google Scholar 

  20. Rothman K . No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–46.

    Article  CAS  Google Scholar 

  21. Lieberman MD, Cunningham WA . Type I and type II error concerns in fMRI research: re-balancing the scale. SCAN 2009; 4: 423–428.

    PubMed  Google Scholar 

  22. Gravetter FJ, Wallnau LB . Essentials of Statistics for the Behavioral Sciences, 7 edn. Wadsworth: Belmont, CA, 2011.

    Google Scholar 

  23. Smith LF, Gratz ZS, Bousquet SG . The Art and Practice of Statistics. Wadsworth: Belmont, CA, 2009.

    Google Scholar 

  24. Gordi T, Khamis H . Simple solution to a common statistical problem: interpreting multiple tests. Clin Ther 2004; 26: 780–786.

    Article  Google Scholar 

  25. Holm S . A simple sequentially rejective multiple test procedure. Scand J Stat 1979; 6: 65–70.

    Google Scholar 

  26. Egger M, Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple graphical test. BMJ 1997; 315: 629–634.

    Article  CAS  Google Scholar 

  27. Dickel DE, Veenstra-VanderWeele J, Bivens NC, Wu X, Fischer DJ, Van Etten-Lee M et al. Association studies of serotonin system candidate genes in early-onset obsessive-compulsive disorder. Biol Psychiatry 2007; 61: 322–329.

    Article  CAS  Google Scholar 

  28. Cohen J . Statistical Power Analyses for the Behavioral Sciences, 2nd edn. Erlbaum: Hillsdale, NJ, 1988.

    Google Scholar 

  29. Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, Goldberg P et al. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry 1999; 45: 1178–1189.

    Article  CAS  Google Scholar 

  30. Zintzaras E, Lau J . Trends in meta-analysis of genetic association studies. J Hum Genet 2008; 53: 1–9.

    Article  CAS  Google Scholar 

  31. Rajender G, Bhatia MS, Kanwal K, Malhotra S, Singh TB, Chaudhary D . Study of neurocognitive endophenotypes in drug-naïve obsessive-compulsive disorder patients, their first-degree relatives and health controls. Acta Psychiatr Scand 2011; 124: 152–161.

    Article  CAS  Google Scholar 

  32. Gatacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E et al. Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment. Am J Med Genet B Neuropsychiatr Genet 2009; 150: 808–816.

    Article  Google Scholar 

  33. Samuels J, Wang Y, Riddle MA, Greenberg BD, Fyer AJ, McCracken JT et al. Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2011; 156: 472–477.

    Article  CAS  Google Scholar 

  34. da Rocha FF, Marco LA, Romano-Silva MA, Corrêa H . Obsessive-compulsive disorder and 5-HTTLPR. Rev Bras Psiquiatr 2009; 31: 281–292.

    Article  Google Scholar 

  35. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78: 815–826.

    Article  CAS  Google Scholar 

  36. Tibrewal P, Kumar HB, Shubha GN, Subhashree D, Purushottam M, Thennarasu K et al. Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a south Indian population. Indian J Med Res 2010; 132: 690–695.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Denys D, van Nieuwerburgh F, Deforce D, Westenberg HGM . Association between serotonergic candidate genes and specific phenotypes of obsessive compulsive disorder. J Affect Disord 2006; 91: 39–44.

    Article  CAS  Google Scholar 

  38. Enoch MA, Kaye WH, Rotondo A, Greenberg BD, Murphy DL, Goldman D . 5-HT2A promoter polymorphism −1438G/A, anorexia nervosa, and obsessive-compulsive disorder. Lancet 1998; 351: 1785–1786.

    Article  CAS  Google Scholar 

  39. Enoch MA, Greenberg BD, Murphy DL, Goldman D . Sexually dimorphic relationship of a 5-HT2A promoter polymorphism with obsessive-compulsive disorder. Biol Psychiatry 2001; 49: 385–388.

    Article  CAS  Google Scholar 

  40. Frisch A, Michaelovsky E, Rockah R, Amir I, Hermesh H, Laor N et al. Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. Eur Neuropsychopharmacol 2000; 10: 205–209.

    Article  CAS  Google Scholar 

  41. Gruenblatt E, Romanos M, Renner T, Walitza S . Copy number variations in children and adolescents with early onset obsessive-compulsive disorder. Eur Child Adolesc Psychiatry 2011; 20 (Suppl 1): S44–S45.

    Google Scholar 

  42. Hemmings SMJ Investigating the molecular aetiology of obsessive-compulsive disorder (OCD) and clinically-defined subsets of OCD. Ph.D. thesis, University of Stellenbosch, South Africa, 2006.

  43. Jung HR, Cho JY, Chung JY, Kin JR, Yu KS, Jang IJ et al. No associations between 5-HTT, 5-HT2A gene polymorphisms and obsessive-compulsive disorder in a Korean population. Psychiatry Invest 2006; 3: 78–86.

    CAS  Google Scholar 

  44. Liu W, Zhao N, Xiong J, Shi M, Hu J . Associated analysis of serotonin and catecholamine system candidate genes in obsessive–compulsive disorder in the Chinese population. Psychiatry Res 2011; 188: 170–172.

    Article  CAS  Google Scholar 

  45. Meira-Lima I, Shavitt RG, Miguita K, Ikenage E, Miguel EC, Vallada H . Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder. Genes Brain Behav 2004; 3: 75–79.

    Article  CAS  Google Scholar 

  46. Nicolini H, Cruz C, Camarena B, Orozco B, Kennedy JL, King N et al. DRD2, DRD3 and 5HT2A receptor genes polymorphisms in obsessive-compulsive disorder. Mol Psychiatry 1996; 1: 461–465.

    CAS  PubMed  Google Scholar 

  47. Saiz PA, Garcia-Portilla MP, Arango C, Morales B, Bascaran MT, Martinez-Barrondo S et al. Association study between obsessive-compulsive disorder and serotonergic candidate genes. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 765–770.

    Article  CAS  Google Scholar 

  48. Tot S, Erdal EM, Yazici K, Yazici AE, Metin O . T102C and −1438 G/A polymorphisms of the 5-HT2A receptor gene in Turkish patients with obsessive–compulsive disorder. Eur Psychiatry 2003; 18: 249–254.

    Article  Google Scholar 

  49. Walitza S, Wewetzer C, Warnke A, Gerlach M, Geller F, Gerber G et al. 5-HT2A promoter polymorphism −1438G/A in children and adolescents with obsessive-compulsive disorders. Mol Psychiatry 2002; 7: 1054–1057.

    Article  CAS  Google Scholar 

  50. Alsobrook JP, Zohar AH, Leboyer M, Chabane N, Ebstein RP, Pauls DL . Association between the COMT locus and obsessive-compulsive disorder in females but not males. Am J Med Genet B Neuropsychiatr Genet 2002; 114: 116–120.

    Article  Google Scholar 

  51. Karayiorgou M, Altemusm M, Galke BL, Goldman D, Murphy DL, Ott J et al. Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA 1997; 94: 4572–4575.

    Article  CAS  Google Scholar 

  52. Katerberg H, Cath DC, Denys DA, Heutink P, Polman A, van Nieuwerburgh FC et al. The role of the COMT Val158Met polymorphism in the phenotypic expression of obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2010; 153: 167–176.

    Google Scholar 

  53. Poyurovsky M, Michaelovsky E, Frisch A, Knoll G, Amir I, Buniak F et al. COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study. Neurosci Lett 2005; 389: 21–24.

    Article  CAS  Google Scholar 

  54. Schindler KM, Richter MA, Kennedy JL, Pato MT, Pato CN . Association between homozygosity at the COMT gene locus and obsessive compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2000; 96: 721–724.

    Article  CAS  Google Scholar 

  55. Walitza S, Scherag A, Renner TJ, Hinney A, Remschmidt H, Herpertz-Dahlmann B et al. Transmission disequilibrium studies in early onset of obsessive-compulsive disorder for polymorphisms in genes of the dopaminergic system. J Neural Transm 2008; 115: 1071–1078.

    Article  CAS  Google Scholar 

  56. Camarena B, Rinetti G, Cruz C, Gomez A, de la Fuente JR, Nicolini H . Additional evidence that genetic variation of MAO-A gene supports a gender subtype in obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2001; 105: 279–282.

    Article  CAS  Google Scholar 

  57. Lochner C, Hemmings SM, Kinnear CJ, Moolman-Smook JC, Corfield VA, Knowles JA et al. Gender in obsessive-compulsive disorder: clinical and genetic findings. Eur Neuropsychopharmacol 2004; 14: 105–113.

    Article  CAS  Google Scholar 

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Acknowledgements

I am grateful to the following investigators for providing unpublished details of their research, which facilitated the completion of this study: Beatriz Camarena, Sîan MJ Hemmings, Humberto Nicolini, Dan J Stein, Jeremy M Veenstra-VanderWeele and Susanne Walitza.

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Taylor, S. Molecular genetics of obsessive–compulsive disorder: a comprehensive meta-analysis of genetic association studies. Mol Psychiatry 18, 799–805 (2013). https://doi.org/10.1038/mp.2012.76

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