Current Psychiatry Reports

, 16:504 | Cite as

Genetics of Opiate Addiction

  • Brian Reed
  • Eduardo R. Butelman
  • Vadim Yuferov
  • Matthew Randesi
  • Mary Jeanne Kreek
Genetic Disorders (W Berrettini, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetic Disorders


Addiction to MOP-r agonists such as heroin (and also addiction to prescription opioids) has reemerged as an epidemic in the twenty first century, causing massive morbidity. Understanding the genetics contributing to susceptibility to this disease is crucial for the identification of novel therapeutic targets, and also for discovery of genetic markers which would indicate relative protection or vulnerability from addiction, and relative responsiveness to pharmacotherapy. This information could thus eventually inform clinical practice. In this review, we focus primarily on association studies of heroin and opiate addiction, and further describe the studies which have been replicated in this field, and are thus more likely to be useful for translational efforts.


Addiction Dependence Opiate Opioid Oxycodone Heroin Genetics SNP MOP-r Prescription opioids Association studies 


Compliance with Ethics Guidelines

Conflict of Interest

Brian Reed, Eduardo R. Butelman, Vadim Yuferov, Matthew Randesi, and Mary Jeanne Kreek declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Paulozzi LJ, Jones CM, Mack KA, Rudd RA. Vital signs: Overdoses of prescription opioid pain relievers – united states, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60(3):1487–92.Google Scholar
  2. 2.
    Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction. Proc Natl Acad Sci U S A. 1998;95(16):9608–13.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.••
    Levran O, Peles E, Randesi M, Shu X, Ott J, Shen PH, et al. Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction. Pharmacogenomics. 2013;14(7):755–68. doi: 10.2217/pgs.13.58. This study confirmed a prior finding of association of SNPs in CYP2B6 with methadone dose requirements, and provides an example of the utility of controlling for known genotype/allelic associations in determining additional variants contributing to genetics associations.PubMedCrossRefGoogle Scholar
  4. 4.
    Bart G, Heilig M, LaForge KS, Pollak L, Leal SM, Ott J, et al. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central sweden. Mol Psychiatry. 2004;9(6):547–9. doi: 10.1038/ Scholar
  5. 5.
    Kroslak T, Laforge KS, Gianotti RJ, Ho A, Nielsen DA, Kreek MJ. The single nucleotide polymorphism a118g alters functional properties of the human mu opioid receptor. J Neurochem. 2007;103(1):77–87. doi: 10.1111/j.1471-4159.2007.04738.x.PubMedGoogle Scholar
  6. 6.
    Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. Allelic expression imbalance of human mu opioid receptor (oprm1) caused by variant a118g. J Biol Chem. 2005;280(38):32618–24. doi: 10.1074/jbc.M504942200.PubMedCrossRefGoogle Scholar
  7. 7.••
    Weerts EM, McCaul ME, Kuwabara H, Yang X, Xu X, Dannals RF, et al. Influence of oprm1 asn40asp variant (a118g) on [11c]carfentanil binding potential: Preliminary findings in human subjects. Int J Neuropsychopharmacol. 2013;16(1):47–53. doi: 10.1017/s146114571200017x. This study provides an illustration of the potentially powerful utility of combining genetics associations studies with in vivo PET imaging to advance our understanding of the underlying biological mechanisms of the disease in question; this particular study provides human in vivo evidence that rs1799971 yields reduced expression of MOP-r levels, consistent with prior in vitro studies.PubMedCrossRefGoogle Scholar
  8. 8.
    Bart G, LaForge KS, Borg L, Lilly C, Ho A, Kreek MJ. Altered levels of basal cortisol in healthy subjects with a 118 g allele in exon 1 of the mu opioid receptor gene. Neuropsychopharmacology. 2006;31(10):2313–7. doi: 10.1038/sj.npp.1301128.PubMedGoogle Scholar
  9. 9.
    Wand GS, McCaul M, Yang X, Reynolds J, Gotjen D, Lee S, et al. The mu-opioid receptor gene polymorphism (a118g) alters hpa axis activation induced by opioid receptor blockade. Neuropsychopharmacology. 2002;26(1):106–14. doi: 10.1016/S0893-133X(01)00294-9.PubMedCrossRefGoogle Scholar
  10. 10.•
    Ducat E, Ray B, Bart G, Umemura Y, Varon J, Ho A, et al. Mu-opioid receptor a118g polymorphism in healthy volunteers affects hypothalamic-pituitary-adrenal axis adrenocorticotropic hormone stress response to metyrapone. Addict Biol. 2013;18:325–31. doi: 10.1111/j.1369-1600.2011.00313.x. This study is an example of functional physiological studies in vivo in humans demonstrating the consequences of a specific functional variant, rs1799971, on normal physiology, determined via endocrine challenge in healthy volunteers.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Kreek MJ. Role of a functional human gene polymorphism in stress responsivity and addictions. Clin Pharmacol Ther. 2008;83(4):615–8. doi: 10.1038/clpt.2008.5.PubMedCrossRefGoogle Scholar
  12. 12.
    Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry. 2007;164(8):1149–59. doi: 10.1176/appi.ajp.2007.05030503.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.••
    Haerian BS, Haerian MS. Oprm1 rs1799971 polymorphism and opioid dependence: Evidence from a meta-analysis. Pharmacogenomics. 2013;14(7):813–24. doi: 10.2217/pgs.13.57. In the context of opiate addiction genetics, the particular variant rs1799971 was the first replicated variant, and has been the most extensively studied; this meta-analysis/review provides an extensive discussion of the findings of this variant.PubMedCrossRefGoogle Scholar
  14. 14.
    Nagaya D, Ramanathan S, Ravichandran M, Navaratnam V. A118g mu opioid receptor polymorphism among drug addicts in malaysia. J Integr Neurosci. 2012;11(1):117–22. doi: 10.1142/s0219635212500082.PubMedCrossRefGoogle Scholar
  15. 15.
    Nikolov MA, Beltcheva O, Galabova A, Ljubenova A, Jankova E, Gergov G, et al. No evidence of association between 118a > g oprm1 polymorphism and heroin dependence in a large bulgarian case-control sample. Drug Alcohol Depend. 2011;117(1):62–5. doi: 10.1016/j.drugalcdep.2010.12.026.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Manini AF, Jacobs MM, Vlahov D, Hurd YL. Opioid receptor polymorphism a118g associated with clinical severity in a drug overdose population. J Med Toxicol: Off J Am Coll Med Toxicol. 2013. doi: 10.1007/s13181-012-0286-3.Google Scholar
  17. 17.
    Crystal HA, Hamon S, Randesi M, Cook J, Anastos K, Lazar J, et al. A c17t polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in african american women. Addict Biol. 2012;17(1):181–91. doi: 10.1111/j.1369-1600.2010.00265.x.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Clarke TK, Crist RC, Kampman KM, Dackis CA, Pettinati HM, O'Brien CP, et al. Low frequency genetic variants in the mu-opioid receptor (oprm1) affect risk for addiction to heroin and cocaine. Neurosci Lett. 2013;542:71–5. doi: 10.1016/j.neulet.2013.02.018.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Levran O, Londono D, O'Hara K, Nielsen DA, Peles E, Rotrosen J, et al. Genetic susceptibility to heroin addiction: A candidate gene association study. Genes Brain Behav. 2008;7(7):720–9. doi: 10.1111/j.1601-183X.2008.00410.x.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Xuei X, Flury-Wetherill L, Bierut L, Dick D, Nurnberger Jr J, Foroud T, et al. The opioid system in alcohol and drug dependence: Family-based association study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of. Psychiatr Genet. 2007;144B(7):877–84.Google Scholar
  21. 21.
    Wang XM, Zhou Y, Spangler R, Ho A, Han JS, Kreek MJ. Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mrna levels in the rat brain. Brain Res Mol Brain Res. 1999;66(1–2):184–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhou Y, Leri F, Grella S, Aldrich J, Kreek MJ. Involvement of dynorphin and kappa opioid receptor in yohimbine-induced reinstatement of heroin seeking in rats. Synapse. 2013;67:358–61.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Yuferov V, Fussell D, LaForge KS, Nielsen DA, Gordon D, Ho A, et al. Redefinition of the human kappa opioid receptor gene (oprk1) structure and association of haplotypes with opiate addiction. Pharmacogenetics. 2004;14(12):793–804.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang H, Kranzler HR, Yang BZ, Luo X, Gelernter J. The oprd1 and oprk1 loci in alcohol or drug dependence: Oprd1 variation modulates substance dependence risk. Mol Psychiatry. 2008;13(5):531–43. doi: 10.1038/ Scholar
  25. 25.•
    Kumar D, Chakraborty J, Das S. Epistatic effects between variants of kappa-opioid receptor gene and a118g of mu-opioid receptor gene increase susceptibility to addiction in indian population. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(2):225–30. doi: 10.1016/j.pnpbp.2011.10.018. This study illustrates the power of combining variants of related genes on determining combined epistatic effects underlying the genetic basis of opiate addiction.PubMedCrossRefGoogle Scholar
  26. 26.
    Rouault M, Nielsen DA, Ho A, Kreek MJ, Yuferov V. Cell-specific effects of variants of the 68-base pair tandem repeat on prodynorphin gene promoter activity. Addict Biol. 2011;16(2):334–46. doi: 10.1111/j.1369-1600.2010.00248.x.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Yuferov V, Ji F, Nielsen DA, Levran O, Ho A, Morgello S, et al. A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced pdyn expression in human brain. Neuropsychopharmacology. 2009;34(5):1185–97. doi: 10.1038/npp.2008.187.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Williams TJ, LaForge KS, Gordon D, Bart G, Kellogg S, Ott J, et al. Prodynorphin gene promoter repeat associated with cocaine/alcohol codependence. Addict Biol. 2007;12(3–4):496–502. doi: 10.1111/j.1369-1600.2007.00069.x.PubMedCrossRefGoogle Scholar
  29. 29.
    Wei SG, Zhu YS, Lai JH, Xue HX, Chai ZQ, Li SB. Association between heroin dependence and prodynorphin gene polymorphisms. Brain Res Bull. 2011;85(3–4):238–42. doi: 10.1016/j.brainresbull.2011.02.010.PubMedCrossRefGoogle Scholar
  30. 30.•
    Clarke TK, Ambrose-Lanci L, Ferraro TN, Berrettini WH, Kampman KM, Dackis CA, et al. Genetic association analyses of pdyn polymorphisms with heroin and cocaine addiction. Genes Brain Behav. 2012. doi: 10.1111/j.1601-183X.2012.00785.x. The findings of this study provide gene-wide, but not variant specific, replication of a contribution of PDYN to heroin addiction.PubMedGoogle Scholar
  31. 31.•
    Nelson EC, Lynskey MT, Heath AC, Wray N, Agrawal A, Shand FL, et al. Association of oprd1 polymorphisms with heroin dependence in a large case-control series. Addict Biol. 2014;19(1):111–21. doi: 10.1111/j.1369-1600.2012.00445.x. This study provided replication of the association of particular OPRD1 variants with heroin addiction.PubMedCrossRefGoogle Scholar
  32. 32.•
    Beer B, Erb R, Pavlic M, Ulmer H, Giacomuzzi S, Riemer Y, et al. Association of polymorphisms in pharmacogenetic candidate genes (oprd1, gal, abcb1, oprm1) with opioid dependence in european population: A case-control study. PLoS One. 2013;8(9):e75359. doi: 10.1371/journal.pone.0075359. This study provided replication of the contribution of variants in GAL and OPRD1 to opiate addiction, with novel findings of a particular OPRM1 variant and ABCB1 variant.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Crist RC, Clarke TK, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ, et al. An intronic variant in oprd1 predicts treatment outcome for opioid dependence in african-americans. Neuropsychopharmacology. 2013;38(10):2003–10. doi: 10.1038/npp.2013.99.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Clarke TK, Crist RC, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ, et al. Genetic variation in oprd1 and the response to treatment for opioid dependence with buprenorphine in european-american females. Pharm J. 2014;14(3):303–8. doi: 10.1038/tpj.2013.30.Google Scholar
  35. 35.
    Comings DE, Blake H, Dietz G, Gade-Andavolu R, Legro RS, Saucier G, et al. The proenkephalin gene (penk) and opioid dependence. Neuroreport. 1999;10(5):1133–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Xuei X, Flury-Wetherill L, Bierut L, Dick D, Nurnberger Jr J, Foroud T, et al. The opioid system in alcohol and drug dependence: Family-based association study. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(7):877–84. doi: 10.1002/ajmg.b.30531.PubMedCrossRefGoogle Scholar
  37. 37.
    Nikoshkov A, Drakenberg K, Wang X, Horvath MC, Keller E, Hurd YL. Opioid neuropeptide genotypes in relation to heroin abuse: Dopamine tone contributes to reversed mesolimbic proenkephalin expression. Proc Natl Acad Sci U S A. 2008;105(2):786–91. doi: 10.1073/pnas.0710902105.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Levran O, Londono D, O'Hara K, Randesi M, Rotrosen J, Casadonte P, et al. Heroin addiction in african americans: A hypothesis-driven association study. Genes Brain Behav. 2009;8(5):531–40. doi: 10.1111/j.1601-183X.2009.00501.x.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.••
    Jacobs MM, Okvist A, Horvath M, Keller E, Bannon MJ, Morgello S, et al. Dopamine receptor d1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. Mol Psychiatry. 2013;18(11):1205–10. doi: 10.1038/mp.2012.140. The combination of genetics association studies with opiate dependence and analysis of post-mortem brain levels of products of the genes in question is a powerful approach to determining the functional consequence of the genetic variants in question, as well as their mechanistic relation to the addiction phenotype.PubMedCrossRefGoogle Scholar
  40. 40.
    Vereczkei A, Demetrovics Z, Szekely A, Sarkozy P, Antal P, Szilagyi A, et al. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence. PLoS One. 2013;8(6):e66592. doi: 10.1371/journal.pone.0066592.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Barnes NM, Sharp T. A review of central 5-ht receptors and their function. Neuropharmacology. 1999;38(8):1083–152.PubMedCrossRefGoogle Scholar
  42. 42.
    Proudnikov D, LaForge KS, Hofflich H, Levenstien M, Gordon D, Barral S, et al. Association analysis of polymorphisms in serotonin 1b receptor (htr1b) gene with heroin addiction: A comparison of molecular and statistically estimated haplotypes. Pharmacogenet Genomics. 2006;16(1):25–36.PubMedCrossRefGoogle Scholar
  43. 43.
    Gerra G, Garofano L, Santoro G, Bosari S, Pellegrini C, Zaimovic A, et al. Association between low-activity serotonin transporter genotype and heroin dependence: Behavioral and personality correlates. Am J Med Genet B Neuropsychiatr Genet. 2004;126B(1):37–42. doi: 10.1002/ajmg.b.20111.PubMedCrossRefGoogle Scholar
  44. 44.
    Gao F, Zhu YS, Wei SG, Li SB, Lai JH. Polymorphism g861c of 5-ht receptor subtype 1b is associated with heroin dependence in han chinese. Biochem Biophys Res Commun. 2011;412(3):450–3. doi: 10.1016/j.bbrc.2011.07.114.PubMedCrossRefGoogle Scholar
  45. 45.
    Cao J, LaRocque E, Li D. Associations of the 5-hydroxytryptamine (serotonin) receptor 1b gene (htr1b) with alcohol, cocaine, and heroin abuse. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(2):169–76. doi: 10.1002/ajmg.b.32128.PubMedCrossRefGoogle Scholar
  46. 46.
    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(3):765–70. doi: 10.1016/j.pnpbp.2007.12.005.PubMedCrossRefGoogle Scholar
  47. 47.
    Yeh YW, Lu RB, Tao PL, Shih MC, Huang SY. A possible association of the norepinephrine transporter gene in the development of heroin dependence in han chinese. Pharmacogenet Genomics. 2011;21(4):197–205. doi: 10.1097/FPC.0b013e32833ef418.PubMedGoogle Scholar
  48. 48.
    Oosterhuis BE, LaForge KS, Proudnikov D, Ho A, Nielsen DA, Gianotti R, et al. Catechol-o-methyltransferase (comt) gene variants: Possible association of the val158met variant with opiate addiction in hispanic women. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(6):793–8. doi: 10.1002/ajmg.b.30716.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Horowitz R, Kotler M, Shufman E, Aharoni S, Kremer I, Cohen H, et al. Confirmation of an excess of the high enzyme activity comt val allele in heroin addicts in a family-based haplotype relative risk study. Am J Med Genet. 2000;96(5):599–603.PubMedCrossRefGoogle Scholar
  50. 50.•
    Zhao B, Zhu Y, Wang W, Cui HM, Wang YP, Lai JH. Analysis of variations in the glutamate receptor, n-methyl d-aspartate 2a (grin2a) gene reveals their relative importance as genetic susceptibility factors for heroin addiction. PLoS One. 2013;8(8):e70817. doi: 10.1371/journal.pone.0070817. The findings of this study replicated a previously determined association of GRIN2A variants with opiate addiction, to date the only replicated association of variants in the expansive glutamate neurotransmitter system with this disease.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Olsen RW, Sieghart W. Gaba a receptors: Subtypes provide diversity of function and pharmacology. Neuropharmacology. 2009;56(1):141–8. doi: 10.1016/j.neuropharm.2008.07.045.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Simon J, Wakimoto H, Fujita N, Lalande M, Barnard EA. Analysis of the set of gaba(a) receptor genes in the human genome. J Biol Chem. 2004;279(40):41422–35. doi: 10.1074/jbc.M401354200.PubMedCrossRefGoogle Scholar
  53. 53.
    Tan KR, Rudolph U, Luscher C. Hooked on benzodiazepines: Gabaa receptor subtypes and addiction. Trends Neurosci. 2011;34(4):188–97. doi: 10.1016/j.tins.2011.01.004.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Calver AR, Davies CH, Pangalos M. Gaba(b) receptors: From monogamy to promiscuity. Neuro-Signals. 2002;11(6):299–314. doi: 10.1159/000068257.PubMedCrossRefGoogle Scholar
  55. 55.
    Wu W, Zhu YS, Li SB. Polymorphisms in the glutamate decarboxylase 1 gene associated with heroin dependence. Biochem Biophys Res Commun. 2012;422(1):91–6. doi: 10.1016/j.bbrc.2012.04.112.PubMedCrossRefGoogle Scholar
  56. 56.
    Enoch MA, Hodgkinson CA, Yuan Q, Shen PH, Goldman D, Roy A. The influence of gabra2, childhood trauma, and their interaction on alcohol, heroin, and cocaine dependence. Biol Psychiatry. 2010;67(1):20–7. doi: 10.1016/j.biopsych.2009.08.019.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Levran O, Peles E, Hamon S, Randesi M, Adelson M, Kreek MJ. Cyp2b6 snps are associated with methadone dose required for effective treatment of opioid addiction. Addict Biol. 2013;18(4):709–16. doi: 10.1111/j.1369-1600.2011.00349.x.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Li D, Sulovari A, Cheng C, Zhao H, Kranzler HR, Gelernter J. Association of gamma-aminobutyric acid a receptor alpha2 gene (gabra2) with alcohol use disorder. Neuropsychopharmacology. 2014;39(4):907–18. doi: 10.1038/npp.2013.291.PubMedCrossRefGoogle Scholar
  59. 59.
    Cheng CY, Hong CJ, Yu YW, Chen TJ, Wu HC, Tsai SJ. Brain-derived neurotrophic factor (val66met) genetic polymorphism is associated with substance abuse in males. Brain Res Mol Brain Res. 2005;140(1–2):86–90. doi: 10.1016/j.molbrainres.2005.07.008.PubMedCrossRefGoogle Scholar
  60. 60.
    Hou H, Qing Z, Jia S, Zhang X, Hu S, Hu J. Influence of brain-derived neurotrophic factor (val66met) genetic polymorphism on the ages of onset for heroin abuse in males. Brain Res. 2010;1353:245–8. doi: 10.1016/j.brainres.2010.07.022.PubMedCrossRefGoogle Scholar
  61. 61.
    Jia W, Shi JG, Wu B, Ao L, Zhang R, Zhu YS. Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence. Neurosci Lett. 2011;495(3):221–4. doi: 10.1016/j.neulet.2011.03.072.PubMedCrossRefGoogle Scholar
  62. 62.•
    Levran O, Peles E, Hamon S, Randesi M, Zhao C, Zhang B, et al. Nerve growth factor beta polypeptide (ngfb) genetic variability: Association with the methadone dose required for effective maintenance treatment. Pharm J. 2012;12(4):319–27. doi: 10.1038/tpj.2011.6. First study to show an association of growth factors besides BDNF with aspects of opiate dependence, in this case methadone dose requirements.Google Scholar
  63. 63.
    Kreek MJ, Koob GF. Drug dependence: Stress and dysregulation of brain reward pathways. Drug Alcohol Depend. 1998;51(1-2):23–47.PubMedCrossRefGoogle Scholar
  64. 64.••
    Levran O, Peles E, Randesi M, Li Y, Rotrosen J, Ott J, et al. Stress-related genes and heroin addiction: A role for a functional fkbp5 haplotype. Psychoneuroendocrinology. 2014;45:67–76. doi: 10.1016/j.psyneuen.2014.03.017. This study focused specifically on the stress reponsive genes for potential genetics association with heroin addiction; in addition to replication previous associations such as GAL and AVPR1a, a novel association with a chaperone protein crucial to the function of the HPA axis was discovered.PubMedCrossRefGoogle Scholar
  65. 65.
    Levran O, Randesi M, Li Y, Rotrosen J, Ott J, Adelson M, et al. Drug addiction and stress-response genetic variability: Association study in african americans. Ann Hum Genet. 2014;78(4):290–8. doi: 10.1111/ahg.12064.PubMedCrossRefGoogle Scholar
  66. 66.
    Binder EB. The role of fkbp5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34 Suppl 1:S186–95. doi: 10.1016/j.psyneuen.2009.05.021.PubMedCrossRefGoogle Scholar
  67. 67.
    Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, et al. Polymorphisms in fkbp5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004;36(12):1319–25. doi: 10.1038/ng1479.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang YJ, Li H, Yang YT, Tie CL, Li F, Xu ZQ, et al. Association of galanin and major depressive disorder in the chinese han population. PLoS One. 2013;8(5):e64617. doi: 10.1371/journal.pone.0064617.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Maher BS, Vladimirov VI, Latendresse SJ, Thiselton DL, McNamee R, Kang M, et al. The avpr1a gene and substance use disorders: Association, replication, and functional evidence. Biol Psychiatry. 2011;70(6):519–27. doi: 10.1016/j.biopsych.2011.02.023.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Wang Y, Zhu Y, Wang W, Wu F, Cui H, Xun X, et al. A population-based association study of casein kinase 1 epsilon loci with heroin dependence in han chinese. J Mol Neurosci: MN. 2014;53(2):143–9. doi: 10.1007/s12031-013-0186-2.PubMedCrossRefGoogle Scholar
  71. 71.
    Nelson EC, Lynskey MT, Heath AC, Wray N, Agrawal A, Shand FL, et al. Ankk1, ttc12, and ncam1 polymorphisms and heroin dependence: Importance of considering drug exposure. JAMA Psychiatry (Chicago, Ill). 2013;70(3):325–33. doi: 10.1001/jamapsychiatry.2013.282.CrossRefGoogle Scholar
  72. 72.
    Morris CP, Baune BT, Domschke K, Arolt V, Swagell CD, Hughes IP, et al. Kpna3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence. Dis Markers. 2012;33(4):163–70. doi: 10.3233/DMA-2012-0921.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Parmacek MS. Myocardin-related transcription factors: Critical coactivators regulating cardiovascular development and adaptation. Circ Res. 2007;100(5):633–44. doi: 10.1161/01.RES.0000259563.61091.e8.PubMedCrossRefGoogle Scholar
  74. 74.
    Nielsen DA, Ji F, Yuferov V, Ho A, Chen A, Levran O, et al. Genotype patterns that contribute to increased risk for or protection from developing heroin addiction. Mol Psychiatry. 2008;13(4):417–28. doi: 10.1038/ Scholar
  75. 75.
    Fonseca F, Gratacos M, Escaramis G, De Cid R, Martin-Santos R, Fernandez-Espejo E, et al. Response to methadone maintenance treatment is associated with the myocd and grm6 genes. Mol Diagn Ther. 2010;14(3):171–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Wang TY, Lee SY, Chen SL, Chen SH, Chu CH, Huang SY, et al. The aldehyde dehydrogenase 2 gene is associated with heroin dependence. Drug Alcohol Depend. 2012;120(1–3):220–4. doi: 10.1016/j.drugalcdep.2011.06.008.PubMedCrossRefGoogle Scholar
  77. 77.
    Wang TY, Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, et al. The adh1b and drd2 gene polymorphism may modify the protective effect of the aldh2 gene against heroin dependence. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:134–9. doi: 10.1016/j.pnpbp.2012.12.011.PubMedCrossRefGoogle Scholar
  78. 78.
    Gelernter J, Kranzler HR, Sherva R, Koesterer R, Almasy L, Zhao H, et al. Genome-wide association study of opioid dependence: Multiple associations mapped to calcium and potassium pathways. Biol Psychiatry. 2014;76(1):66–74. doi: 10.1016/j.biopsych.2013.08.034.PubMedCrossRefGoogle Scholar
  79. 79.
    Edenberg HJ. The collaborative study on the genetics of alcoholism: An update. Alcohol Res Health. 2002;26(3):214–8.PubMedGoogle Scholar
  80. 80.
    Bierut LJ, Strickland JR, Thompson JR, Afful SE, Cottler LB. Drug use and dependence in cocaine dependent subjects, community-based individuals, and their siblings. Drug Alcohol Depend. 2008;95(1–2):14–22. doi: 10.1016/j.drugalcdep.2007.11.023.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF, et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 2007;16(1):24–35. doi: 10.1093/hmg/ddl441.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Crettol S, Deglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hammig R, et al. Methadone enantiomer plasma levels, cyp2b6, cyp2c19, and cyp2c9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78(6):593–604. doi: 10.1016/j.clpt.2005.08.011.PubMedCrossRefGoogle Scholar
  83. 83.••
    Dobrinas M, Crettol S, Oneda B, Lahyani R, Rotger M, Choong E, et al. Contribution of cyp2b6 alleles in explaining extreme (s)-methadone plasma levels: A cyp2b6 gene resequencing study. Pharmacogenet Genomics. 2013;23(2):84–93. doi: 10.1097/FPC.0b013e32835cb2e2. This study extends prior studies of the association of known variants of the CYP2B6 gene, illustrating the need for, in addition to conducting studies of known variants, continued investigation in additional populations of gene sequences to determine novel variants, or altered allelic frequencies, which may also play important roles.PubMedCrossRefGoogle Scholar
  84. 84.
    Levran O, O'Hara K, Peles E, Li D, Barral S, Ray B, et al. Abcb1 (mdr1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet. 2008;17(14):2219–27. doi: 10.1093/hmg/ddn122.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig R, Gothuey I, et al. Abcb1 and cytochrome p450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther. 2006;80(6):668–81.PubMedCrossRefGoogle Scholar
  86. 86.
    Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA. Abcb1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther. 2006;80(6):682–90. doi: 10.1016/j.clpt.2006.09.011.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Brian Reed
    • 1
  • Eduardo R. Butelman
    • 1
  • Vadim Yuferov
    • 1
  • Matthew Randesi
    • 1
  • Mary Jeanne Kreek
    • 1
  1. 1.The Laboratory of the Biology of Addictive DiseasesThe Rockefeller UniversityNew YorkUSA

Personalised recommendations