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An overview of the genetics of substance use disorders

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Abstract

Twin, family, and adoption studies show that genetic factors play a signi.cant role in vulnerability to becoming addicted to drugs. Through a combination of genetic approaches, the variant alleles responsible for interindividual differences in susceptibility to addiction are being uncovered.

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References and Recommended Reading

  1. Goldman D, Oroszi G, Ducci F: The genetics of addictions: uncovering the genes. Nat Rev Genet 2005, 6:521–532. A comprehensive review of the genetics and epidemiology of addiction.

    Article  PubMed  CAS  Google Scholar 

  2. Kreek MJ, Nielsen DA, Butelman ER, Laforge KS: Genetic in.uences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neuroscience 2005, 8:1450–1457. An excellent review by one of the leading investigators in the field. The review discusses addiction from the perspective of the genetics of personality traits associated with high-risk behaviors linked to increased susceptibility to addiction.

    Article  CAS  Google Scholar 

  3. Caderet RJ, Yates WR, Troughton E, et al.: Adoption study demonstrating two genetic pathways to drug abuse. Arch Gen Psychiatry 1995, 52:42–52.

    Google Scholar 

  4. Pickens SW, Svikis DS, McGue M, LaBuda M: Common genetic mechanisms in alcohol, drug and mental disorder comorbidity. Drug Alcohol Dep 1995, 39:129–138.

    Article  CAS  Google Scholar 

  5. Tsuang MT, Lyons MJ, Eisen SA, et al.: Genetic in.uences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. Am J Med Genet (Neuropsychiat Genet) 1996, 67:473–477. An important genetic epidemiologic study, the largest twin study in addiction ever conducted.

    Article  CAS  Google Scholar 

  6. Bierut LJ, Dinwiddie SH, Begleiter H, et al.: Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch Gen Psychiatry 1998, 55:982–988. A paper from the COGA group showing the familial transmission of dependence on several different addicting substances.

    Article  PubMed  CAS  Google Scholar 

  7. Uhl GR: Molecular genetics of substance abuse vulnerability: remarkable recent convergence of genome scan results. Ann NY Acad Sci 2004, 1025:1–13.

    Article  PubMed  CAS  Google Scholar 

  8. Grove W, Eckert E, Heston L, et al.: Heritability of substance abuse and antisocial behavior: a study of monozygotic twins reared apart. Biol Psychiatry 1990, 27:1293–1304. A small study of monozygotic twins reared apart, but one of the first to show heritability of antisocial personality disorder.

    Article  PubMed  CAS  Google Scholar 

  9. van den Bree MB, Johnson EO, Neale MC, Pickens RW: Genetic and environmental in.uences on drug use and abuse/dependence in male and female twins. Drug Alcohol Depend 1998, 52:231–241. A very commonly cited study in the addiction genetics field.

    Article  PubMed  Google Scholar 

  10. Swan GE, Carmelli D, Cardon LR: Heavy consumption of cigarettes, alcohol and coffee in male twins. J Stud Alcohol 1997, 58:182–190.

    PubMed  CAS  Google Scholar 

  11. Tsuang MT, Lyons MJ, Meyer JM, et al.: Co-occurrence of abuse of different drugs in men: the role of drug-speci.c and shared vulnerabilities. Arch Gen Psych 1998, 55:967–972. An important study demonstrating that common and drug-speci.c genetic factors play a role in substance dependence.

    Article  CAS  Google Scholar 

  12. Kendler KS, Jacobson KC, Prescott CA, Neale MC: Speci.city of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am J Psychiatry 2003, 160:687–695.

    Article  PubMed  Google Scholar 

  13. Nesler EJ: Is there a common molecular pathway for addiction? Nat Neurosci 2005, 8:1445–1449. A wonderful overview of the neurobiology and molecular biology of addiction by one of the leading investigators in the field.

    Article  CAS  Google Scholar 

  14. Kosten TA, Ambrosio E: HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats [review]. Psychoneuroendocrinology 2002, 27:35–69.

    Article  PubMed  CAS  Google Scholar 

  15. Brower VG, Fu Y, Matta SG, Sharp BM: Rat strain differences in nicotine self-administration using an unlimited access paradigm. Brain Res 2002, 930:12–20.

    Article  PubMed  CAS  Google Scholar 

  16. Merikangas KR, Risch N: Genomic priorities and public health. Science 2003, 302:599–601.

    Article  PubMed  CAS  Google Scholar 

  17. Frances H, Le Foll B, Diaz J, et al.: Role of DRD3 in morphine-induced conditioned place preference using drd3-knockout mice. Neuroreport 2004, 15:2245–2249.

    Article  PubMed  CAS  Google Scholar 

  18. Maldonado R, Saiardi A, Valverde O, et al.: Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 1997, 388:586–589.

    Article  PubMed  CAS  Google Scholar 

  19. Matthes HW, Maldonado R, Simonin F, et al.: Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996, 383:819–823.

    Article  PubMed  CAS  Google Scholar 

  20. Tsai HJ, Kho JY, Shaikh N, et al.: Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations. Hum Genet 2005, 5:1–14.

    Google Scholar 

  21. Blum K, Noble EP, Sheridan PJ, et al.: Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA 1990, 263:2055–2060.

    Article  PubMed  CAS  Google Scholar 

  22. Xu K, Liu XH, Nagarajan S, et al.: Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. Am J Med Genet 2002, 110:45–50.

    Article  PubMed  Google Scholar 

  23. Stober G, Jatzke S, Heils A, et al.: Insertion/deletion variant (-141C Ins/Del) in the 5′ regulatory region of the dopamine D2 receptor gene: lack of association with schizophrenia and bipolar affective disorder. J Neural Transm 1998, 105:101–109.

    Article  PubMed  CAS  Google Scholar 

  24. Parsian A, Cloninger CR, Zhang ZH: Functional variant in the DRD2 receptor promoter region and subtypes of alcoholism. Am J Med Genet 2000, 96:407–411.

    Article  PubMed  CAS  Google Scholar 

  25. Li T, Liu X, Zhao J, et al.: Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects. Am J Med Genet 2002, 114:329–335.

    Article  PubMed  Google Scholar 

  26. Xu K, Lichtermann D, Lipsky RH, et al.: Association of speci.c haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry 2004, 61:597–606.

    Article  PubMed  CAS  Google Scholar 

  27. Gelernter J, Kranzler HR, Satel SL, Rao PA: Genetic association between dopamine transporter protein alleles and cocaine-induced paranoia. Neuropsychopharmacology 1994, 11:195–200.

    Article  PubMed  CAS  Google Scholar 

  28. Hong CJ, Cheng CY, Shu LR, et al.: Association study of the dopamine and serotonin transporter genetic polymorphisms and methamphetamine abuse in Chinese males. J Neural Transm 2003, 110:345–351.

    Article  PubMed  CAS  Google Scholar 

  29. Ujike H, Harano M, Inada T, et al.: Nine-or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis. Pharmacogenomics J 2003, 3:242–247.

    Article  PubMed  CAS  Google Scholar 

  30. Cubells JF, Zabetian CP: Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology. Psychopharmacology (Berl) 2004, 174:463–476.

    CAS  Google Scholar 

  31. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005, 10:40–68.

    Article  PubMed  CAS  Google Scholar 

  32. Vandenberg DJ, Miller I, Uhl G, Lachman HM: A high activity COMT allele is associated with substance abuse vulnerability. Am J Med Genet (Neuropsychiat Genet) 1997, 74:439–442.

    Article  Google Scholar 

  33. Tiihonen J, Hallikainen T, Lachman HM, et al.: Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism. Mol Psychiatry 1999, 4:286–289.

    Article  PubMed  CAS  Google Scholar 

  34. Hallikainen T, Lachman H, Saito T, et al.: Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early onset alcoholism associated with severe antisocial behavior. Am J Med Genet 2000, 96:348–352.

    Article  PubMed  CAS  Google Scholar 

  35. Horowitz R, Kotler M, Shufman E, et al.: Con.rmation 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, 96:599–603.

    Article  PubMed  CAS  Google Scholar 

  36. Li T, Chen CK, Hu X, et al.: Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Am J Med Genet B Neuropsychiatr Genet 2004, 129:120–124.

    Article  PubMed  Google Scholar 

  37. Wang T, Franke P, Neidt H, et al.: Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach. Mol Psychiatry 2001, 6:109–111.

    Article  PubMed  CAS  Google Scholar 

  38. Ishiguro H, Haruo Shibuya T, Toru M, et al.: Association study between high and low activity polymorphism of catechol-O-methyltransferase gene and alcoholism. Psychiatr Genet 1999, 9:135–138.

    Article  PubMed  CAS  Google Scholar 

  39. Duaux E, Gorwood P, Griffon N, et al.: Homozygosity at the dopamine D3 receptor gene is associated with opiate dependence. Mol Psychiatry 1999, 3:333–336.

    Article  Google Scholar 

  40. Comings DE, Gonzalez N, Wu S, et al.: Homozygosity at the dopamine DRD3 receptor gene in cocaine dependence. Mol Psychiatry 1999, 4:484–487.

    Article  PubMed  CAS  Google Scholar 

  41. Li T, Liu X, Zhao J, et al.: Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects. Am J Med Genet 2002, 114:329–335.

    Article  PubMed  Google Scholar 

  42. Bart G, Kreek MJ, Ott J, et al.: Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 2005, 30:417–422.

    Article  PubMed  CAS  Google Scholar 

  43. Berrettini WH, Ferraro TN, Alexander RC, et al.: Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains. Nat Genet 1994, 7:54–58. The first quantitative trait loci mapping study in addiction.

    Article  PubMed  CAS  Google Scholar 

  44. Bond C, LaForge KS, Tian M, 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, 95:9608–9613. A description of the first functional variant in the mu-opioid receptor gene.

    Article  PubMed  CAS  Google Scholar 

  45. Szeto CY, Tang NL, Lee DT, Stadlin A: Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport 2001, 12:1103–1106.

    Article  PubMed  CAS  Google Scholar 

  46. Bart G, Heilig M, LaForge KS, 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, 9:547–549.

    Article  PubMed  CAS  Google Scholar 

  47. Crowley JJ, Oslin DW, Patkar AA, et al.: A genetic association study of the mu opioid receptor and severe opioid dependence. Psychiatr Genet 2003, 13:169–173.

    Article  PubMed  Google Scholar 

  48. Shi J, Hui L, Xu Y, et al.: Sequence variations in the muopioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 2002, 19:459–460.

    Article  PubMed  CAS  Google Scholar 

  49. Hernandez-Avila CA, Wand G, Luo X, et al.: Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the mu-opioid receptor locus (OPRM1). Am J Med Genet (Neuropsychiatr Genet) 2003, 118:60–65.

    Article  Google Scholar 

  50. Wand GS, McCaul M, Yang X, et al.: The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 2002, 26:106–114.

    Article  PubMed  CAS  Google Scholar 

  51. Oslin DW, Berrettini W, Kranzler HR, et al.: A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003, 28:1546–1552.

    Article  PubMed  CAS  Google Scholar 

  52. Yuferov V, Fussell D, LaForge KS, et al.: Rede.nition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics 2004, 14:793–804.

    Article  PubMed  CAS  Google Scholar 

  53. Mayer P, Rochlitz H, Rauch E, et al.: Association between a delta opioid receptor gene polymorphism and heroin dependence in man. Neuroreport 1997, 8:2547–2550.

    Article  PubMed  CAS  Google Scholar 

  54. Xu K, Liu XH, Nagarajan S, et al.: Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. Am J Med Genet 2002, 110:45–50.

    Article  PubMed  Google Scholar 

  55. Comings DE, Blake H, Dietz G, et al.: The proenkephalin gene (PENK) and opioid dependence. Neuroreport 1999, 10:1133–1135.

    Article  PubMed  CAS  Google Scholar 

  56. Zimprich A, Kraus J, Woltje M, et al.: An allelic variation in the human prodynorphin gene promoter alters stimulusinduced expression. J Neurochem 2000, 74:472–477.

    Article  PubMed  CAS  Google Scholar 

  57. Chen AC, LaForge KS, Ho A, et al.: Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse. Am J Med Genet 2002, 114:429–435.

    Article  PubMed  Google Scholar 

  58. Ray R, Doyle GA, Crowley JJ, et al.: A functional prodynorphin promoter polymorphism and opioid dependence. Psychiatr Genet 2005, 15:295–298.

    Article  PubMed  Google Scholar 

  59. Edenberg HJ: The Collaborative Study on the Genetics of Alcoholism: an update. Alcohol Res Health 2002, 26:214–218.

    PubMed  Google Scholar 

  60. Li MD, Ma JZ, Cheng R, et al.: A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet 2003, 4 Suppl 1:S103.

    Article  PubMed  Google Scholar 

  61. Gelernter J, Panhuysen C, Weiss R, et al.: Genomewide linkage scan for cocaine dependence and related traits: signi.cant linkages for a cocaine-related trait and cocaine-induced paranoia. Am J Med Genet (Neuropsychiat Genet) 2005, 136:45–52. The results of the first linkage study in cocaine dependence.

    Google Scholar 

  62. Edenberg HJ, Dick DM, Xuei X, et al.: Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet 2004, 74:705–714. The first evidence that genetic variability in a GABA receptor subunit gene is involved in alcohol dependence; a great example of genetic con.rmation that a biologically feasible candidate gene is involved in alcoholism.

    Article  PubMed  CAS  Google Scholar 

  63. Covault J, Gelernter J, Hesselbrock V, et al.: Allelic and haplotypic association of GABRA2 with alcohol dependence. Am J Med Genet (Neuropsychiat Genet) 2004, 129:104–109. Con.rmation of the role of GABA gene variability in alcoholism variability.

    Article  Google Scholar 

  64. Beuten J, Ma JZ, Payne TJ, et al.: Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are signi.cantly associated with nicotine dependence. Am J Hum Genet 2005, 76:859–864. Further con.rmation of the role of GABA.

    Article  PubMed  CAS  Google Scholar 

  65. Li MD, Beuten J, Ma JZ, et al.: Ethnic- and gender-speci.c association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 2005, 14:1211–1219. A feasible candidate gene for nicotine addiction vulnerability is con.rmed by genetic findings.

    Article  PubMed  CAS  Google Scholar 

  66. Uhl GR, Liu QR, Walther D, et al.: Polysubstance abusevulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am J Hum Genet 2001, 69:1290–1300. The first genome-wide association study in addiction. A similar strategy, albeit with more markers, is now being carried out in many behavioral disorders.

    Article  PubMed  CAS  Google Scholar 

  67. Liu QR, Drgon T, Walther D, et al.: Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples. Proc Natl Acad Sci U S A 2005, 102:11864–11869. A follow-up to the study in reference 66.

    Article  PubMed  CAS  Google Scholar 

  68. Grossman A: Brain opiates and neuroendocrine function. Clin Endocrinol Metab 1983, 12:725–746.

    Article  PubMed  CAS  Google Scholar 

  69. Coventry TL, Jessop DS, Finn DP, et al.: Endomorphins and activation of the hypothalamo-pituitary-adrenal axis. J Endocrinol 2001, 169:185–193.

    Article  PubMed  CAS  Google Scholar 

  70. Shirayama Y, Ishida H, Iwata M, et al.: Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects. J Neurochem 2004, 90:1258–1268.

    Article  PubMed  CAS  Google Scholar 

  71. Tseng RJ, Padgett DA, Dhabhar FS, et al.: Stress-induced modulation of NK activity during in.uenza viral infection: role of glucocorticoids and opioids. Brain Behav Immun 2005, 19:153–164.

    Article  PubMed  CAS  Google Scholar 

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  1. Departments of Medicine and Psychiatry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, Bronx, NY, USA

    H. M. Lachman MD

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Lachman, H.M. An overview of the genetics of substance use disorders. Curr Psychiatry Rep 8, 133–143 (2006). https://doi.org/10.1007/s11920-006-0013-3

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