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The genetics of addictions: uncovering the genes

Key Points

  • Addictions are common chronic psychiatric diseases that are characterized by persistent, compulsive and uncontrolled use.

  • Addictions are a worldwide public-health issue, causing 12.4% of deaths.

  • Addictions are among the most heritable psychiatric diseases; heritabilities range from 0.39 (hallucinogens) to 0.72 (cocaine).

  • Monozygotic:dizygotic twin concordance ratios for addictions are approximately 2:1, indicating that interactions among multiple genes (polygenicity) might not be required for vulnerability.

  • Animal studies model addiction-relevant behaviours and have led to an understanding of addiction neurobiology and the identification of several genes that mediate variation in drug preference and response.

  • The neurobiological pathways that modulate reward, stress resiliency and behaviour inhibition are among those that also underlie general addiction liability.

  • Across the addictions, the correlation of addiction liability with heritability indicates that variation in the core neurobiology of addiction is genetically influenced.

  • Cross-inheritance studies in twins indicate that both substance-specific and substance-nonspecific genetic factors are important in addictions, and that there is cross-inheritance between addictions and other psychiatric disorders. Linkage studies have identified genes that are of both these general types.

  • Treatment and prevention of addictions are partially successful because medical management targets the acute phase of illness and is not individualized.

  • The individualization of treatment and prevention is likely to be advanced by the discovery of genetic predictors of the neurobiological pathways that underlie addiction.

Abstract

The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods. The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioural control and the anxiety or stress response. Our future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors and a role in shared vulnerabilities such as variation in reward or stress resiliency.

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Figure 1: Lifetime prevalence of substance use in 6 countries.
Figure 2: Heritability of addictive disorders.
Figure 3: Genetic complexity in unrelated individuals and its effect on twin concordance.
Figure 4: Weighted means of monozygotic and dizygotic tetrachoric correlation ratios for 10 addictive disorders.
Figure 5: Clusters of the γ-aminobutyric acid (GABA) subunit genes in humans.

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References

  1. Roberts, A. J. & Koob, G. F. The neurobiology of addiction: an overview. Alcohol Health Res. World 21, 101–106 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Grant, B. F. et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch. Gen. Psychiatry 61, 807–816 (2004).

    Article  PubMed  Google Scholar 

  3. McGinnis, J. M. & Foege, W. H. Mortality and morbidity attributable to use of addictive substances in the United States. Proc. Assoc. Am. Physicians 111, 109–118 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Merikangas, K. R. & Risch, N. Genomic priorities and public health. Science 302, 599–601 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Kendler, K. S., Prescott, C. A., Myers, J. & Neale, M. C. The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch. Gen. Psychiatry 60, 929–937 (2003). Presents an explanation for the origin of comorbidity between substance-use disorders and other psychiatric disorders.

    Article  PubMed  Google Scholar 

  6. Krueger, R. F. et al. Etiologic connections among substance dependence, antisocial behavior, and personality: modeling the externalizing spectrum. J. Abnorm. Psychol. 111, 411–424 (2002).

    Article  PubMed  Google Scholar 

  7. Young, S. E., Stallings, M. C., Corley, R. P., Krauter, K. S. & Hewitt, J. K. Genetic and environmental influences on behavioral disinhibition. Am. J. Med. Genet. 96, 684–695 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Grant, B. F., Hasin, D. S., Chou, S. P., Stinson, F. S. & Dawson, D. A. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch. Gen. Psychiatry 61, 1107–1115 (2004).

    Article  PubMed  Google Scholar 

  9. Vega, W. A. et al. Prevalence and age of onset for drug use in seven international sites: results from the international consortium of psychiatric epidemiology. Drug Alcohol Depend. 68, 285–297 (2002).

    Article  PubMed  Google Scholar 

  10. Reuter, J. et al. Pathological gambling is linked to reduced activation of the mesolimbic reward system. Nature Neurosci. 8, 147–148 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Hasin, D. Classification of alcohol use disorders. Alcohol Res. Health 27, 5–17 (2003).

    PubMed  PubMed Central  Google Scholar 

  12. Li, M. D., Cheng, R., Ma, J. Z. & Swan, G. E. A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98, 23–31 (2003).

    Article  PubMed  Google Scholar 

  13. Kendler, K. S., Karkowski, L. M., Neale, M. C. & Prescott, C. A. Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Arch. Gen. Psychiatry 57, 261–269 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Goldstein, A. & Kalant, H. Drug policy: striking the right balance. Science 249, 1513–1521 (1990). Discusses the advantages and pitfalls of drug legalization.

    Article  CAS  PubMed  Google Scholar 

  15. Merikangas, K. R. & Avenevoli, S. Implications of genetic epidemiology for the prevention of substance use disorders. Addict. Behav. 25, 807–820 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Kessler, R. C. et al. Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch. Gen. Psychiatry 54, 313–321 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Goldman, D. & Bergen, A. General and specific inheritance of substance abuse and alcoholism. Arch. Gen. Psychiatry 55, 964–965 (1998). An overview of the general and specific inheritance of different addictions.

    Article  CAS  PubMed  Google Scholar 

  18. Swan, G. E., Carmelli, D. & Cardon, L. R. Heavy consumption of cigarettes, alcohol and coffee in male twins. J. Stud. Alcohol 58, 182–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Picciotto, M. R. & Corrigall, W. A. Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J. Neurosci. 22, 3338–3341 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu, D. et al. Ethanol inhibition of nicotinic acetylcholine type α7 receptors involves the amino-terminal domain of the receptor. Mol. Pharmacol. 50, 1010–1016 (1996).

    CAS  PubMed  Google Scholar 

  21. Tsuang, M. T. et al. Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch. Gen. Psychiatry 55, 967–972 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Kendler, K. S., Jacobson, K. C., Prescott, C. A. & Neale, M. C. Specificity 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 160, 687–695 (2003).

    Article  PubMed  Google Scholar 

  23. Long, J. C. et al. Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am. J. Med. Genet. 81, 216–221 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Lappalainen, J. et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch. Gen. Psychiatry 55, 989–994 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Thorgeirsson, T. E. et al. Anxiety with panic disorder linked to chromosome 9q in Iceland. Am. J. Hum. Genet. 72, 1221–1230 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hennah, W., Varilo, T., Paunio, T. & Peltonen, L. Haplotype analysis and identification of genes for a complex trait: examples from schizophrenia. Ann. Med. 36, 322–331 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Uhl, G. R. Molecular genetics of substance abuse vulnerability: remarkable recent convergence of genome scan results. Ann. NY Acad. Sci. 1025, 1–13 (2004). An overview of converging results from genome scans for various addictions.

    Article  CAS  PubMed  Google Scholar 

  28. Reich, T. et al. Genome-wide search for genes affecting the risk for alcohol dependence. Am. J. Med. Genet. 81, 207–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Nurnberger, J. I. Jr et al. Evidence for a locus on chromosome 1 that influences vulnerability to alcoholism and affective disorder. Am. J. Psychiatry 158, 718–724 (2001).

    Article  PubMed  Google Scholar 

  30. Uhl, G. R., Liu, Q. R., Walther, D., Hess, J. & Naiman, D. Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am. J. Hum. Genet. 69, 1290–300 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Crabbe, J. C., Phillips, T. J., Buck, K. J., Cunningham, C. L. & Belknap, J. K. Identifying genes for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci. 22, 173–179 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Korpi, E. R., Kleingoor, C., Kettenmann, H. & Seeburg, P. H. Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor. Nature 361, 356–359 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Hu, X. et al. 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 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Schuckit, M. A. et al. Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABAα6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol. Psychiatry 45, 647–651 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Iwata, N., Cowley, D. S., Radel, M., Roy-Byrne, P. P. & Goldman, D. Relationship between a GABAAα6 Pro385Ser substitution and benzodiazepine sensitivity. Am. J. Psychiatry 156, 1447–1449 (1999).

    CAS  PubMed  Google Scholar 

  36. Fee, J. R. et al. Predictors of high ethanol consumption in RIIβ knock-out mice: assessment of anxiety and ethanol-induced sedation. Alcohol. Clin. Exp. Res. 28, 1459–1468 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schuckit, M. A. & Smith, T. L. An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch. Gen. Psychiatry 53, 202–210 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Edenberg, H. J. et al. Variations in GABRA2, encoding the α2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations. Am. J. Hum. Genet. 74, 705–714 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Radel, M. et al. Haplotype-based localization of an alcohol dependence gene to the 5q34 γ-aminobutyric acid type A gene cluster. Arch. Gen. Psychiatry 62, 47–55 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Tu, G. C. & Israel, Y. Alcohol consumption by orientals in North America is predicted largely by a single gene. Behav. Genet. 25, 59–65 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Thomasson, H. R. et al. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am. J. Hum. Genet. 48, 677–681 (1991). Shows that functional polymorphisms in ADH1B and ALDH2 function additively to modify the risk of alcoholism by inducing the flushing response.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Peterson, R. J., Goldman, D. & Long, J. C. Effects of worldwide population subdivision on ALDH2 linkage disequilibrium. Genome Res. 9, 844–852 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Peterson, R. J., Goldman, D. & Long, J. C. Nucleotide sequence diversity in non-coding regions of ALDH2 as revealed by restriction enzyme and SSCP analysis. Hum. Genet. 104, 177–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Oota, H. et al. The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination. Ann. Hum. Genet. 68, 93–109 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Osier, M. V. et al. A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. Am. J. Hum. Genet. 71, 84–99 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Goldman, D. & Enoch, M. A. Genetic epidemiology of ethanol metabolic enzymes: a role for selection. World Rev. Nutr. Diet. 63, 143–160 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Grant, B. F. et al. Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch. Gen. Psychiatry 61, 361–368 (2004).

    Article  PubMed  Google Scholar 

  48. Merikangas, K. R. et al. Comorbidity of substance use disorders with mood and anxiety disorders: results of the International Consortium in Psychiatric Epidemiology. Addict. Behav. 23, 893–907 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Swendsen, J. D. & Merikangas, K. R. The comorbidity of depression and substance use disorders. Clin. Psychol. Rev. 20, 173–189 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Clark, D. B., Cornelius, J. R., Kirisci, L. & Tarter, R. E. Childhood risk categories for adolescent substance involvement: a general liability typology. Drug Alcohol Depend. 77, 13–21 (2005).

    Article  PubMed  Google Scholar 

  51. Wong, M. M., Zucker, R. A., Puttler, L. I. & Fitzgerald, H. E. Heterogeneity of risk aggregation for alcohol problems between early and middle childhood: nesting structure variations. Dev. Psychopathol 11, 727–744 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Slutske, W. S. et al. Common genetic risk factors for conduct disorder and alcohol dependence. J. Abnorm. Psychol. 107, 363–374 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Grove, W. M. et al. Heritability of substance abuse and antisocial behavior: a study of monozygotic twins reared apart. Biol. Psychiatry 27, 1293–1304 (1990).

    Article  CAS  PubMed  Google Scholar 

  54. Cloninger, C. R., Bohman, M. & Sigvardsson, S. Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. Arch. Gen. Psychiatry 38, 861–868 (1981). A study of adoptees showing cross-inheritance of alcoholism and ASPD.

    Article  CAS  PubMed  Google Scholar 

  55. Virkkunen, M. & Linnoila, M. Brain serotonin, type II alcoholism and impulsive violence. J. Stud. Alcohol Suppl. 11, 163–169 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Grant, B. F. & Dawson, D. A. Age of onset of drug use and its association with DSM-IV drug abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J. Subst. Abuse 10, 163–173 (1998). An epidemiological study showing that a delay in the onset of use is crucial to minimizing the lifetime burden of alcoholism.

    Article  CAS  PubMed  Google Scholar 

  57. Faraone, S. V., Doyle, A. E., Mick, E. & Biederman, J. Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am. J. Psychiatry 158, 1052–1057 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H. & van Oost, B. A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262, 578–580 (1993).

    Article  CAS  PubMed  Google Scholar 

  59. Caspi, A. et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Crabbe, J. C. et al. Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nature Genet. 14, 98–101 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Soyka, M., Preuss, U. W., Koller, G., Zill, P. & Bondy, B. Association of 5-HT1B receptor gene and antisocial behavior in alcoholism. J. Neural. Transm. 111, 101–109 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Kranzler, H. R., Hernandez-Avila, C. A. & Gelernter, J. Polymorphism of the 5-HT1B receptor gene (HTR1B): strong within-locus linkage disequilibrium without association to antisocial substance dependence. Neuropsychopharmacology 26, 115–222 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Porjesz, B. et al. Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes. Biol. Psychol. 61, 229–248 (2002).

    Article  PubMed  Google Scholar 

  64. Becker, K., Laucht, M., El-Faddagh, M. & Schmidt, M. H. The dopamine D4 receptor gene exon III polymorphism is associated with novelty seeking in 15-year-old males from a high-risk community sample. J. Neural Transm. 112, 847–858. (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Sander, T. et al. Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics. Am. J. Med. Genet. 74, 483–487 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Kendler, K. S. et al. The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Arch. Gen. Psychiatry 52, 374–383 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Goldman, D. & Barr, C. S. Restoring the addicted brain. N. Engl. J. Med. 347, 843–845 (2002).

    Article  PubMed  Google Scholar 

  68. McEwen, B. S. Stress, adaptation, and disease. Allostasis and allostatic load. Ann. NY Acad. Sci. 840, 33–44 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001). Highlights the relevance of using animal models to understand the neuroadaptational processes that are crucial to addiction.

    Article  CAS  PubMed  Google Scholar 

  70. Koss, M. P. et al. Adverse childhood exposures and alcohol dependence among seven Native American tribes. Am. J. Prev. Med. 25, 238–244 (2003).

    Article  PubMed  Google Scholar 

  71. Barr, C. S. et al. Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcohol Clin. Exp. Res. 27, 812–817 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Chen, J. et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet. 75, 807–821 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhu, G. et al. Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5′ nuclease assay. Psychopharmacology (Berl.) 177, 178–184 (2004).

    Article  CAS  Google Scholar 

  74. Xu, K. et al. A catechol-O-methyltransferase haplotype is associated with heroin dependence. J. Med. Genet. (submitted).

  75. Shifman, S. et al. A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet. 71, 1296–1302 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Diatchenko, L. et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum. Mol. Genet. 14, 135–143 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Egan, M. F. et al. Effect of COMT Val108/158Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98, 6917–6922 (2001). A neurocognitive and neuroimaging paper showing that a functional COMT polymorphism alters frontal lobe function and cognition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Malhotra, A. K. et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am. J. Psychiatry 159, 652–654 (2002).

    Article  PubMed  Google Scholar 

  79. Goldberg, T. E. et al. Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch. Gen. Psychiatry 60, 889–896 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Vandenbergh, D. J., Rodriguez, L. A., Miller, I. T., Uhl, G. R. & Lachman, H. M. High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers. Am. J. Med. Genet. 74, 439–442 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. Kauhanen, J. et al. Association between the functional polymorphism of catechol-O-methyltransferase gene and alcohol consumption among social drinkers. Alcohol Clin. Exp. Res. 24, 135–139 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Enoch, M. A., Xu, K., Ferro, E., Harris, C. R. & Goldman, D. Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism. Psychiatr. Genet. 13, 33–41 (2003).

    Article  PubMed  Google Scholar 

  84. Zubieta, J. K. et al. COMT Val158Met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299, 1240–1243 (2003). An imaging study showing that a functional polymorphism in COMT alters pain/stress resiliency.

    Article  CAS  PubMed  Google Scholar 

  85. Lesch, K. P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Feinn, R., Nellissery, M. & Kranzler, H. R. Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am. J. Med. Genet. B 133, 79–84 (2005).

    Article  Google Scholar 

  87. Sen, S., Burmeister, M. & Ghosh, D. Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am. J. Med. Genet. B 127, 85–89 (2004).

    Article  Google Scholar 

  88. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003). A pioneering study of gene–environment interactions.

    Article  CAS  PubMed  Google Scholar 

  89. Heinz, A. et al. A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol. Psychiatry 47, 643–649 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Little, K. Y. et al. Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am. J. Psychiatry 155, 207–213 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Hariri, A. R. et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400–403 (2002). An imaging paper showing that a functional polymorphism in the serotonin transporter alters the response to fearful stimuli in the amygdala.

    Article  CAS  PubMed  Google Scholar 

  92. Pezawas, L. et al. Interaction of SERT & BDNF: Susceptibility for depression is reflected in morphometric changes of critical limbic circuits in humans. Neuropsychopharmacology 29, S200 (2004).

    Google Scholar 

  93. Smolka, M. L. et al. Additive effects of catechol-O-methyltransferase Val158Met (COMT) and serotonin transporter (5-HTT) genotype on processing of adversive stimuli in the amygdala and hippocampus Science (submitted).

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

    Article  CAS  PubMed  Google Scholar 

  95. Hu, X. et al. The serotonin transporter promoter polymorphism is functionally triallelic and the gain-of-function allele is linked to obsessive-compulsive disorder. Neuron (submitted).

  96. Weisner, C., Matzger, H. & Kaskutas, L. A. How important is treatment? One-year outcomes of treated and untreated alcohol-dependent individuals. Addiction 98, 901–911 (2003).

    Article  PubMed  Google Scholar 

  97. Simpson, D. D., Joe, G. W. & Broome, K. M. A national 5-year follow-up of treatment outcomes for cocaine dependence. Arch. Gen. Psychiatry 59, 538–544 (2002).

    Article  PubMed  Google Scholar 

  98. O'Brien, C. P. A range of research-based pharmacotherapies for addiction. Science 278, 66–70 (1997). An overview of the development of medication to treat addictions.

    Article  CAS  PubMed  Google Scholar 

  99. Johnson, B. A. An overview of the development of medications including novel anticonvulsants for the treatment of alcohol dependence. Expert. Opin. Pharmacother. 5, 1943–1955 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Pettinati, H. M. et al. Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin. Exp. Res. 24, 1041–1049 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Dundon, W., Lynch, K. G., Pettinati, H. M. & Lipkin, C. Treatment outcomes in type A and B alcohol dependence 6 months after serotonergic pharmacotherapy. Alcohol Clin. Exp. Res. 28, 1065–1073 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kulich, M., Rosenfeld, M., Goss, C. H. & Wilmott, R. Improved survival among young patients with cystic fibrosis. J. Pediatr. 142, 631–636 (2003).

    Article  PubMed  Google Scholar 

  103. Nishimura, R. et al. Incidence of ESRD and survival after renal replacement therapy in patients with type 1 diabetes: a report from the Allegheny County Registry. Am. J. Kidney Dis. 42, 117–124 (2003).

    Article  PubMed  Google Scholar 

  104. Kupfer, D. J., First, M. B. & Regier, D. A. (eds) A research agenda for DSM-V (American Psychiatric Association, 2002). A comprehensive synthesis and analysis of the priorities in research to improve the classification of psychiatric diseases.

    Google Scholar 

  105. Babor, T. F. et al. Types of alcoholics. I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Arch. Gen. Psychiatry 49, 599–608 (1992).

    Article  CAS  PubMed  Google Scholar 

  106. Zucker, R. A. The four alcoholisms: a developmental account of the etiologic process. Nebr. Symp. Motiv. 34, 27–83 (1986).

    CAS  PubMed  Google Scholar 

  107. Windle, M. & Scheidt, D. M. Alcoholic subtypes: are two sufficient? Addiction 99, 1508–1519 (2004).

    Article  PubMed  Google Scholar 

  108. Morey, L. C. & Skinner, H. A. Empirically derived classifications of alcohol-related problems. Recent. Dev. Alcohol 4, 145–168 (1986).

    Article  CAS  PubMed  Google Scholar 

  109. Hauser, J. & Rybakowski, J. Three clusters of male alcoholics. Drug Alcohol Depend. 48, 243–250 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Feingold, A., Ball, S. A., Kranzler, H. R. & Rounsaville, B. J. Generalizability of the type A/type B distinction across different psychoactive substances. Am. J. Drug Alcohol Abuse 22, 449–462 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Ball, S. A., Carroll, K. M., Babor, T. F. & Rounsaville, B. J. Subtypes of cocaine abusers: support for a type A–type B distinction. J. Consult. Clin. Psychol. 63, 115–124 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Kalivas, P. W. & McFarland, K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl.) 168, 44–56 (2003).

    Article  CAS  Google Scholar 

  113. Nestler, E. J. Molecular mechanisms of drug addiction. Neuropharmacology 47 (Suppl. 1), 24–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Kalivas, P. W. Glutamate systems in cocaine addiction. Curr. Opin. Pharmacol. 4, 23–29 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Liu, Q. R. et al. Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's disease. Am. J. Med. Genet. B 134, 93–103 (2005).

    Article  Google Scholar 

  116. Lappalainen, J. et al. A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch. Gen. Psychiatry 59, 825–831 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Connor, J. P., Young, R. M., Lawford, B. R., Ritchie, T. L. & Noble, E. P. D2 dopamine receptor (DRD2) polymorphism is associated with severity of alcohol dependence. Eur. Psychiatry 17, 17–23 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Berrettini, W. H., Ferraro, T. N., Alexander, R. C., Buchberg, A. M. & Vogel, W. H. Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains. Nature Genet. 7, 54–58 (1994). QTL mapping of mouse opioid preference to the location of the μ-opioid receptor, among other genomic regions.

    Article  CAS  PubMed  Google Scholar 

  119. Ferraro, T. N. et al. Confirmation of a major QTL influencing oral morphine intake in C57 and DBA mice using reciprocal congenic strains. Neuropsychopharmacology 30, 742–746 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Fehr, C., Shirley, R. L., Belknap, J. K., Crabbe, J. C. & Buck, K. J. Congenic mapping of alcohol and pentobarbital withdrawal liability loci to a < 1 centimorgan interval of murine chromosome 4: identification of Mpdz as a candidate gene. J. Neurosci. 22, 3730–3738 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Carr, L. G. et al. A quantitative trait locus for alcohol consumption in selectively bred rat lines. Alcohol Clin. Exp. Res. 22, 884–887 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Demarest, K., Koyner, J., McCaughran, J. Jr, Cipp, L. & Hitzemann, R. Further characterization and high-resolution mapping of quantitative trait loci for ethanol-induced locomotor activity. Behav. Genet. 31, 79–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Moore, M. S. et al. Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway. Cell 93, 997–1007 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Matthes, H. W. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ-opioid-receptor gene. Nature 383, 819–823 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Picciotto, M. R. et al. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173–177 (1998). Shows that the mouse knockout for the β2 nicotinic receptor gene loses both nicotine preference and nicotine binding in the brain.

    Article  CAS  PubMed  Google Scholar 

  126. Olive, M. F. & Messing, R. O. Protein kinase C isozymes and addiction. Mol. Neurobiol. 29, 139–154 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Thiele, T. E., Marsh, D. J., Ste Marie, L., Bernstein, I. L. & Palmiter, R. D. Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396, 366–369 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. van den Bree, M. B., Johnson, E. O., Neale, M. C. & Pickens, R. W. Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug Alcohol Depend. 52, 231–241 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Lynskey, M. T. et al. Genetic and environmental contributions to cannabis dependence in a national young adult twin sample. Psychol. Med. 32, 195–207 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Kendler, K. S. & Prescott, C. A. Cannabis use, abuse, and dependence in a population-based sample of female twins. Am. J. Psychiatry 155, 1016–1022 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Tsuang, M. T. et al. Genetic influences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. Am. J. Med. Genet. 67, 473–477 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. Kendler, K. S., Karkowski, L. & Prescott, C. A. Hallucinogen, opiate, sedative and stimulant use and abuse in a population-based sample of female twins. Acta. Psychiatr. Scand. 99, 368–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Kendler, K. S. & Prescott, C. A. Cocaine use, abuse and dependence in a population-based sample of female twins. Br. J. Psychiatry 173, 345–350 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. True, W. R. et al. Common genetic vulnerability for nicotine and alcohol dependence in men. Arch. Gen. Psychiatry 56, 655–661 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Kendler, K. S., Thornton, L. M. & Pedersen, N. L. Tobacco consumption in Swedish twins reared apart and reared together. Arch. Gen. Psychiatry 57, 886–892 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Kendler, K. S. et al. A population-based twin study in women of smoking initiation and nicotine dependence. Psychol. Med. 29, 299–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Heath, A. C. & Martin, N. G. Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence. Addict. Behav. 18, 19–34 (1993).

    Article  CAS  PubMed  Google Scholar 

  138. Heath, A. C. et al. Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol. Med. 27, 1381–1396 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Prescott, C. A. & Kendler, K. S. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am. J. Psychiatry 156, 34–40 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Kendler, K. S., Heath, A. C., Neale, M. C., Kessler, R. C. & Eaves, L. J. A population-based twin study of alcoholism in women. Jama 268, 1877–1882 (1992).

    Article  CAS  PubMed  Google Scholar 

  141. Carmelli, D., Heath, A. C. & Robinette, D. Genetic analysis of drinking behavior in World War II veteran twins. Genet. Epidemiol. 10, 201–213 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Hettema, J. M., Corey, L. A. & Kendler, K. S. A multivariate genetic analysis of the use of tobacco, alcohol, and caffeine in a population based sample of male and female twins. Drug Alcohol Depend. 57, 69–78 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Kendler, K. S. & Prescott, C. A. Caffeine intake, tolerance, and withdrawal in women: a population-based twin study. Am. J. Psychiatry 156, 223–228 (1999).

    CAS  PubMed  Google Scholar 

  144. Eisen, S. A. et al. Familial influences on gambling behavior: an analysis of 3359 twin pairs. Addiction 93, 1375–1384 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge E. Gordis for his helpful comments on this manuscript.

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DATABASES

Entrez gene

ADH1B

ALDH2

BRCA1

COMT

DRD4

HTR1B

MAOA

Omim

Schizophrenia

Type 1 diabetes

FURTHER INFORMATION

Collaborative Study on the Genetics of Alcoholism

International HapMap Project

National Institute on Drug Abuse Genetic Consortium

National Institute on Drug Abuse report —Addiction burden in the USA

Request proposals for access to a whole genome association scanning resource to identify addiction loci

World Health Organization — Global status report on alcohol, 2004

World Health Organization report — The global burden of addiction

Glossary

AFFECTIVE DISTURBANCE

An abnormal or inappropriate emotion or mood.

POINT PREVALENCE

The proportion of individuals who have a phenotype at a specified point in time or within a defined timeframe (for example, 1 year).

DISABILITY ADJUSTED LIFE YEAR

The years of life that are lost due to premature mortality or disability.

PSYCHOPATHOLOGY

A psychiatric disease, or the manifestation of a psychiatric disease.

POLYGENICITY

A model of genetic determinism in which many alleles function in combination to produce a phenotype.

HETEROGENEITY

A model of genetic determinism in which different alleles lead to the same phenotype in different individuals, but an individual allele can suffice to produce the phenotype.

HERITABILITY

An estimate of the genetic component of liability, which ranges from zero to one.

ADDICTION LIABILITY

The relative potential of an agent to lead to addiction.

ABUSE

Substance abuse is a disease that is operationally defined using objective criteria such as those issued by the American Psychatric Association and the World Health Organization.

RESILIENCY

The ability to withstand mental or physical stress.

OLIGOGENICITY

A model of genetic determinism in which a few alleles function in combination to produce a phenotype.

HAPLOTYPE

A combination of alleles at different loci on the same chromosome.

COMORBIDITY

The co-occurrence of two or more diseases in an individual or an excess of disease co-occurrence in a population.

PHENOCOPY

Describes the situation in which a phenotype of an environmental origin mimics a phenotype of a genetic origin.

GENOCOPY

Describes the situation in which a phenotype of a genetic origin mimics a phenotype of a different genetic origin.

PENETRANCE

The probability of expressing a phenotype that is determined by a genotype.

LOCUS-BASED LINKAGE

The detection of locus-to-locus or locus-to-phenotype genetic linkage. This is generally accomplished by detecting a lack of meiotic recombination in families in which alleles at one locus are observed to be in coupling (co-transmitted) or repulsion (not co-transmitted) with alleles at a second locus.

LINKAGE DISEQUILIBRIUM

The excess and complementary deficit of combinations of alleles at two different loci, which is based on rarity of meiotic recombination between loci on the same chromosome.

BENZODIAZEPINE DRUGS

Structurally similar selective GABAA receptor agonists that have potent anxiolytic, sedative, central muscle relaxant and anti-epileptic properties.

QUANTITATIVE TRAIT LOCUS

A genetic locus that is identified through the statistical analysis of complex traits (such as body weight). These traits are typically affected by more than one gene and by the environment.

PHARMACODYNAMIC

Relating to the response of cells and tissues to drugs.

PHARMACOKINETIC

Relating to drug absorption, distribution or metabolism.

MANIA

A pathological elevated mood-state that is associated with mental and physical hyperactivity.

PANIC DISORDER

An anxiety disorder characterized by paroxysms of overwhelming fear with associated somatic, behavioural and cognitive symptoms.

AGORAPHOBIA

An anxiety disorder that is characterized by fear and avoidance of places from which escape might be difficult.

BULIMIA

An eating disorder that is characterized by recurrent binge eating, which is accompanied by self-induced purging and/or other inappropriate compensatory behaviours.

ALLOSTASIS

A new homeostatic (maintained) equilibrium that lies outside the normal range and is characterized by long-lasting adaptational mechanisms that are activated in response to a stressor.

CATECHOLAMINES

A class of structurally similar amine neurotransmitters, including dopamine, noradrenaline and adrenaline, that are derived from the amino acid tyrosine.

WISCONSIN CARD-SORT TEST

A neurocognitive test of frontal lobe function that requires the subject to switch strategies that are needed to match cards to a target.

N-BACK TEST

A neurocognitive test of frontal lobe function and working memory that requires the recall of an earlier stimulus after a new stimulus (or stimuli) has been presented.

WORKING MEMORY

A memory system that is activated for temporary storage and manipulation of information while a mental task is carried out.

WARRIOR/WORRIER MODEL

A selectionist explanation for the maintenance of COMT alleles that have counterbalancing effects in cognition versus resilience to stress and anxiety.

AMYGDALA

A complex region of the brain temporal lobe that is important in modulating emotional states.

AGONISTS

Molecules that bind to receptors and elicit signal transduction.

ANTAGONISTS

Molecules that bind to receptors and, although they do not have intrinsic action, inhibit signal transduction.

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Goldman, D., Oroszi, G. & Ducci, F. The genetics of addictions: uncovering the genes. Nat Rev Genet 6, 521–532 (2005). https://doi.org/10.1038/nrg1635

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