Journal of Neural Transmission

, Volume 115, Issue 3, pp 531–536 | Cite as

A functional polymorphism of the µ-opioid receptor gene is associated with completed suicides

  • A. Hishimoto
  • H. Cui
  • K. Mouri
  • H. Nushida
  • Y. Ueno
  • K. Maeda
  • O. Shirakawa
Article

Summary.

A recent linkage study suggested that a putative locus for suicidal behavior independent of psychiatric disease phenotypes lies at 5′ upstream of the µ-opioid receptor (OPRM1) gene. We explored an association between suicide and genetic variations of the OPRM1 using a case-control study of 183 completed suicides and 374 control subjects. We genotyped four single nucleotide polymorphisms (SNPs) including a common A118G SNP. The genotypic and allelic distributions of the A118G SNP were significantly different between the completed suicide and control groups (P = 0.014 and 0.039, respectively). A dominant model analysis of the A118G SNP showed an enhanced association with suicide (P = 0.0041, Odds ratio 0.575) and this significant association was observed with a logistic regression analysis that takes sex and age factors into account (P = 0.021). Our results raise the possibility that the A118G SNP of the OPRM1 gene is associated with suicide.

Keywords: Suicide; µ-opioid receptor; A118G; polymorphism; haplotype 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anguelova, M, Benkelfat, C, Turecki, G 2003A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behaviorMol Psychiatry8646653PubMedCrossRefGoogle Scholar
  2. Arias, A, Feinn, R, Kranzler, HR 2006Association of an Asn40Asp (A118G) polymorphism in the mu-opioid receptor gene with substance dependence: a meta-analysisDrug Alcohol Depend83262268PubMedCrossRefGoogle Scholar
  3. Barrett, JC, Fry, B, Maller, J, Daly, MJ 2005Haploview: analysis and visualization of LD and haplotype mapsBioinformatics21263265PubMedCrossRefGoogle Scholar
  4. Beautrais, AL, Joyce, PR, Mulder, RT 1996Risk factors for serious suicide attempts among youths aged 13 through 24 yearsJ Am Acad Child Adolesc Psychiatry3511741182PubMedCrossRefGoogle Scholar
  5. Becker, A, Schroder, H, Brosz, M, Grecksch, G, Schneider-Stock, R 1997Differences between two substrains of AB mice in the opioid systemPharmacol Biochem Be58763766CrossRefGoogle Scholar
  6. Befort, K, Filliol, D, Decaillot, FM, Gaveriaux-Ruff, C, Hoehe, MR, Kieffer, BL 2001A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signalingJ Biol Chem27631303137PubMedCrossRefGoogle Scholar
  7. Bergen, AW, Kokoszka, J, Peterson, R,  et al. 1997Mu opioid receptor gene variants: lack of association with alcohol dependenceMol Psychiatry2490494PubMedCrossRefGoogle Scholar
  8. Beyer, A, Koch, T, Schroder, H, Schulz, S, Hollt, V 2004Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptorJ Neurochem89553560PubMedCrossRefGoogle Scholar
  9. Bond, C, LaForge, KS, Tian, M,  et al. 1998Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addictionProc Natl Acad Sci USA9596089613PubMedCrossRefGoogle Scholar
  10. Bondy, B, Buettner, A, Zill, P 2006Genetics of suicideMol Psychiatry11336351PubMedCrossRefGoogle Scholar
  11. Brent, DA, Mann, JJ 2005Family genetic studies, suicide, and suicidal behaviorAm J Med Genet C Semin Med Genet1331324PubMedGoogle Scholar
  12. Cheng, R, Juo, SH, Loth, JE,  et al. 2006Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health Genetics Initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorderMol Psychiatry11252260PubMedCrossRefGoogle Scholar
  13. Chong, RY, Oswald, L, Yang, X, Uhart, M, Lin, PI, Wand, GS 2006The Micro-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stressNeuropsychopharmacology31204211PubMedGoogle Scholar
  14. Drolet, G, Dumont, EC, Gosselin, I, Kinkead, R, Laforest, S, Trottier, JF 2001Role of endogenous opioid system in the regulation of the stress responseProg Neuropsychopharmacol Biol Psychiatry25729741PubMedCrossRefGoogle Scholar
  15. Dupont, WD, Plummer, WD,Jr 1998Power and sample size calculations for studies involving linear regressionControl Clin Trials19589601PubMedCrossRefGoogle Scholar
  16. Escriba, PV, Ozaita, A, Garcia-Sevilla, JA 2004Increased mRNA expression of alpha2A-adrenoceptors, serotonin receptors and mu-opioid receptors in the brains of suicide victimsNeuropsychopharmacology2915121521PubMedCrossRefGoogle Scholar
  17. Gabilondo, AM, Meana, JJ, Garcia-Sevilla, JA 1995Increased density of mu-opioid receptors in the postmortem brain of suicide victimsBrain Res682245250PubMedCrossRefGoogle Scholar
  18. Gelernter, J, Kranzler, H, Cubells, J 1999Genetics of two mu opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjectsMol Psychiatry4476483PubMedCrossRefGoogle Scholar
  19. Giraud, O, Cervo, L, Grignaschi, G, Samanin, R 1989Activation of mu opioid receptors in the nucleus raphe dorsalis blocks apomorphine-induced aggression in rats: serotonin appears not to be involvedBrain Res488174179PubMedCrossRefGoogle Scholar
  20. Gregg, TR, Siegel, A 2001Brain structures and neurotransmitters regulating aggression in cats: implications for human aggressionProg Neuropsychopharmacol Biol Psychiatry2591140PubMedCrossRefGoogle Scholar
  21. Gross-Isseroff, R, Dillon, KA, Israeli, M, Biegon, A 1990Regionally selective increases in mu opioid receptor density in the brains of suicide victimsBrain Res530312316PubMedCrossRefGoogle Scholar
  22. Gwynn, GJ, Domino, EF 1984Genotype-dependent behavioral sensitivity to mu vs. kappa opiate agonists. I. Acute and chronic effects on mouse locomotor activityJ Pharmacol Exp Ther231306311PubMedGoogle Scholar
  23. Heilä, H, Isometsa, ET, Henriksson, MM, Heikkinen, ME, Marttunen, MJ, Lonnqvist, JK 1997Suicide and schizophrenia: a nationwide psychological autopsy study on age- and sex-specific clinical characteristics of 92 suicide victims with schizophreniaAm J Psychiatry15412351242PubMedGoogle Scholar
  24. Hernandez-Avila, CA, Wand, G, Luo, X, Gelernter, J, Kranzler, HR 2003Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the mu-opioid receptor locus (OPRM1)Am J Med Genet B Neuropsychiatr Genet1186065PubMedCrossRefGoogle Scholar
  25. Hishimoto, A, Shirakawa, O, Nishiguchi, N,  et al. 2006Association between a functional polymorphism in the renin-angiotensin system and completed suicideJ Neural Transm11319151920PubMedCrossRefGoogle Scholar
  26. Ide, S, Kobayashi, H, Tanaka, K,  et al. 2004Gene polymorphisms of the mu opioid receptor in methamphetamine abusersAnn N Y Acad Sci1025316324PubMedCrossRefGoogle Scholar
  27. Ide, S, Kobayashi, H, Ujike, H,  et al. 2006Linkage disequilibrium and association with methamphetamine dependence/psychosis of mu-opioid receptor gene polymorphismsPharmacogenomics J6179188PubMedCrossRefGoogle Scholar
  28. Ikeda, K, Ide, S, Han, W, Hayashida, M, Uhl, GR, Sora, I 2005How individual sensitivity to opiates can be predicted by gene analysesTrends Pharmacol Sci26311317PubMedCrossRefGoogle Scholar
  29. Inder, WJ, Hellemans, J, Ellis, MJ, Evans, MJ, Livesey, JH, Donald, RA 1995Elevated basal adrenocorticotropin and evidence for increased central opioid tone in highly trained male athletesJ Clin Endocrinol Metab80244248PubMedCrossRefGoogle Scholar
  30. Luo, X, Kranzler, HR, Zuo, L, Wang, S, Blumberg, HP, Gelernter, J 2005CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: results from an extended case-control structured association studyHum Mol Genet1424212434PubMedCrossRefGoogle Scholar
  31. Mann, JJ 1998The neurobiology of suicideNat Med42530PubMedCrossRefGoogle Scholar
  32. Mann, JJ 2003Neurobiology of suicidal behaviourNat Rev Neurosci4819828PubMedCrossRefGoogle Scholar
  33. Miller, GM, Bendor, J, Tiefenbacher, S, Yang, H, Novak, MA, Madras, BK 2004A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggressionMol Psychiatry999108PubMedCrossRefGoogle Scholar
  34. Robins, E, Murphy, GE, Wilkinson, RH,Jr, Gassner, S, Kayes, J 1959Some clinical considerations in the prevention of suicide based on a study of 134 successful suicidesAm J Public Health49888899CrossRefGoogle Scholar
  35. Roy, A, Rylander, G, Sarchiapone, M 1997Genetics of suicides. Family studies and molecular geneticsAnn N Y Acad Sci836135157PubMedCrossRefGoogle Scholar
  36. Scarone, S, Gambini, O, Calabrese, G,  et al. 1990Asymmetrical distribution of beta-endorphin in cerebral hemispheres of suicides: preliminary dataPsychiat Res32159166CrossRefGoogle Scholar
  37. Shaffer, D, Gould, MS, Fisher, P,  et al. 1996Psychiatric diagnosis in child and adolescent suicideArch Gen Psychiatry53339348PubMedGoogle Scholar
  38. Tan, EC, Tan, CH, Karupathivan, U, Yap, EP 2003Mu opioid receptor gene polymorphisms and heroin dependence in Asian populationsNeuroreport14569572PubMedCrossRefGoogle Scholar
  39. Town, T, Abdullah, L, Crawford, F,  et al. 1999Association of a functional mu-opioid receptor allele (+118A) with alcohol dependencyAm J Med Genet88458461PubMedCrossRefGoogle Scholar
  40. Wand, GS, McCaul, M, Yang, X,  et al. 2002The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockadeNeuropsychopharmacology26106114PubMedCrossRefGoogle Scholar
  41. Wand, GS, Schumann, H 1998Relationship between plasma adrenocorticotropin, hypothalamic opioid tone, and plasma leptinJ Clin Endocrinol Metab8321382142PubMedCrossRefGoogle Scholar
  42. Yanagi, M, Shirakawa, O, Kitamura, N,  et al. 2005Association of 14-3-3 epsilon gene haplotype with completed suicide in JapaneseJ Hum Genet50210216PubMedCrossRefGoogle Scholar
  43. Zalsman, G, Molcho, A, Huang, Y, Dwork, A, Li, S, Mann, JJ 2005Postmortem mu-opioid receptor binding in suicide victims and controlsJ Neural Transm112949954PubMedCrossRefGoogle Scholar
  44. Zhang, Y, Wang, D, Johnson, AD, Papp, AC, Sadee, W 2005Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118GJ Biol Chem2803261832624PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • A. Hishimoto
    • 1
  • H. Cui
    • 1
  • K. Mouri
    • 1
  • H. Nushida
    • 2
  • Y. Ueno
    • 2
  • K. Maeda
    • 1
  • O. Shirakawa
    • 1
    • 3
  1. 1.Division of Psychiatry and Neurology, Department of Environmental Health and Safety, Faculty of Medical SciencesKobe University Graduate School of MedicineKobeJapan
  2. 2.Division of Legal Medicine, Department of Environmental Health and Safety, Faculty of Medical SciencesKobe University Graduate School of MedicineKobeJapan
  3. 3.Department of NeuropsychiatryKinki University School of MedicineOsakaJapan

Personalised recommendations