Molecular Genetics of Addictions


Addictions to both licit and illicit drugs are common chronic brain disorders that are extremely costly to the individuals and society. Although genetics contributes significantly to vulnerability to these affective disorders, the susceptibility genes underlying them are largely unknown. Various genetics approaches including genome‐wide linkage, candidate gene association, GWAS and sequencing analysis have implicated several common genomic regions and genes in the aetiology of addiction to multiple substances. For example, variants in the α2 subunit of GABAA receptor have been found repeatedly in association with alcoholism and alcohol‐related phenotypes. A gene cluster on chromosomes 15q24/q25.1 that encompasses the genes for nicotine acetylcholine receptor subunits α5, α3 and β4 was implicated in addiction to tobacco and other substances as well. Current efforts aim not only to replicate these findings in independent samples but also to determine the functional mechanisms of these associations.

Key Concepts

  • Drug addiction is a chronic brain disorder.
  • Both human and animal studies reveal that addiction is determined not only by genetic and environmental factors but also by their interactions.
  • There exist significant genetic overlaps among addictions to different substances.
  • It is important to determine not only genetic but also environmental factors involved in the aetiology of addictions.
  • Various genomic regions have been revealed to harbour susceptibility loci for multiple addictive disorders.
  • Genes such as those encoding GABA‐A and GABA‐B receptor subunits, neurexins 1 and 2 and some nicotinic receptor subunits are revealed to be associated with addictions.
  • Determination of gene–environmental interactions is as important and challenging as determining gene–gene interactions.
  • Small microRNAs may play important roles in the mediation of expression of genes implicated in addictions.

Keywords: genetics; addiction; dependence; alcohol; smoking; opioid; interaction

Figure 1. A summary of chromosomal locations of nominated peaks or intervals for addictions to alcohol, cannabis, cocaine, heroin, nicotine and their related phenotypes with ‘significant’ or ‘suggestive’ evidence of linkage by independent studies based on at least two substances of abuse. The determination of ‘significant’ or ‘suggestive’ evidence of linkage at each linkage peak was based on the rigorous criteria proposed by Lander and Kruglyak , which defines an LOD of >3.6 or a P value of <2.2 × 10−5 as a ‘significant linkage’ and an LOD of >2.2 but <3.6 or a P value of 7.4 × 10−4 as a ‘suggestive’ linkage. Each linkage is given either with a colour‐filled circle or a triangle representing a reported linkage peak or region, respectively. Each colour represents a type of abused substance that could come from the same or different reports/studies. The ‘units’ for each chromosome is ‘cM’. Partial contents of this figure have been reported in Li and Burmeister © Nature Publishing Group.
Figure 2. The ND genetic susceptibility map with nominated linkage peaks and candidate genes, as suggested by genome‐wide linkage, hypothesis‐driven candidate gene association (CAS), genome‐wide association (GWAS), and targeted sequencing (next‐generation sequencing; NGS) studies. Linkage peaks are marked in light grey; CAS, GWAS and NGS results are presented as gene names at the outer, middle and inner rings, respectively. Adapted from Yang and Li © Nature Publishing Group.


Agrawal A and Lynskey MT (2006) The genetic epidemiology of cannabis use, abuse and dependence. Addiction 101: 801–812.

Agrawal A, Pergadia ML, Saccone SF, et al. (2008a) Gamma‐aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case‐control study. Addiction 103: 1027–1038.

Agrawal A, Pergadia ML, Saccone SF, et al. (2008b) An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project. Archives of General Psychiatry 65: 713–721.

Batel P, Houchi H, Daoust M, et al. (2008) A haplotype of the DRD1 gene is associated with alcohol dependence. Alcoholism: Clinical and Experimental Research 32: 567–572.

Bierut LJ, Stitzel JA, Wang JC, et al. (2008) Variants in nicotinic receptors and risk for nicotine dependence. American Journal of Psychiatry 165: 1163–1171.

Bierut LJ (2010) Convergence of genetic findings for nicotine dependence and smoking related diseases with chromosome 15q24‐25. Trends in Pharmacological Sciences 31: 46–51.

Burmeister M, McInnis MG and Zollner S (2008) Psychiatric genetics: progress amid controversy. Nature Reviews Genetics 9: 527–540.

Caspi A, McClay J, Moffitt TE, et al. (2002) Role of genotype in the cycle of violence in maltreated children. Science 297: 851–854.

Chandrasekar V and Dreyer JL (2009) microRNAs miR‐124, let‐7d and miR‐181a regulate cocaine‐induced plasticity. Molecular and Cellular Neuroscience 42: 350–362.

Conti DV, Lee W, Li D, et al. (2008) Nicotinic acetylcholine receptor beta2 subunit gene implicated in a systems‐based candidate gene study of smoking cessation. Human Molecular Genetics 17: 2834–2848.

Dick DM, Plunkett J, Hamlin D, et al. (2007) Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Psychiatric Genetics 17: 35–38.

Ducci F, Enoch MA, Hodgkinson C, et al. (2008) Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Molecular Psychiatry 13: 334–347.

Edenberg HJ, Dick DM, Xuei X, et al. (2004) Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. American Journal of Human Genetics 74: 705–714.

Feinn R, Nellissery M and Kranzler HR (2005) Meta‐analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 133B: 79–84.

Flint J and Munafo MR (2008) Forum: Interactions between gene and environment. Current Opinion in Psychiatry 21: 315–317.

Gelernter J and Kranzler HR (2009) Genetics of alcohol dependence. Human Genetics 126: 91–99.

Goldman D, Oroszi G and Ducci F (2005) The genetics of addictions: uncovering the genes. Nature Reviews Genetics 6: 521–532.

Grucza RA, Wang JC, Stitzel JA, et al. (2008) A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biological Psychiatry 64: 922–929.

Haller G, Druley T, Vallania FL, et al. (2012) Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. Human Molecular Genetics 21: 647–655.

Han S, Gelernter J, Luo X and Yang BZ (2010) Meta‐analysis of 15 genome‐wide linkage scans of smoking behavior. Biological Psychiatry 67: 12–19.

Huang W, Ma JZ, Payne TJ, et al. (2008) Significant association of DRD1 with nicotine dependence. Human Genetics 123: 133–140.

Huang W and Li MD (2009a) Differential allelic expression of dopamine D1 receptor gene (DRD1) is modulated by microRNA miR‐504. Biological Psychiatry 65: 702–705.

Huang W and Li MD (2009b) Nicotine modulates expression of miR‐140*, which targets the 3'‐untranslated region of dynamin 1 gene (Dnm1). International Journal of Neuropsychopharmacology 12: 537–546.

Kabbani N, Woll MP, Levenson R, Lindstrom JM and Changeux JP (2007) Intracellular complexes of the beta2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics. Proceedings of the National Academy of Sciences of the United States of America 104: 20570–20575.

Kosik KS (2006) The neuronal microRNA system. Nature Reviews Neuroscience 7: 911–920.

Lander E and Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics 11: 241–247.

Li MD (2006) The genetics of nicotine dependence. Current Psychiatry Reports 8: 158–164.

Li MD (2008) Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome‐wide linkage analyses. Human Genetics 123: 119–131.

Li MD, Cheng R, Ma JZ and Swan GE (2003) A meta‐analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98: 23–31.

Li MD and Burmeister M (2009) New insights into the genetics of addiction. Nature Reviews Genetics 10: 225–231.

Li MD, Mangold JE, Seneviratne C, et al. (2009) Association and interaction analyses of GABBR1 and GABBR2 with nicotine dependence in European‐ and African‐American populations. PLoS One 4: e7055.

Long JC, Knowler WC, Hanson RL, et al. (1998) Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome‐wide scan in an American Indian population. American Journal of Medical Genetics 81: 216–221.

Lou XY, Chen GB, Yan L, et al. (2007) A generalized combinatorial approach for detecting gene‐by‐gene and gene‐by‐environment interactions with application to nicotine dependence. American Journal of Human Genetics 80: 1125–1137.

Lou XY, Chen GB, Yan L, et al. (2008) A combinatorial approach to detecting gene–gene and gene–environment interactions in family studies. American Journal of Human Genetics 83: 457–467.

Nilsson KW, Sjoberg RL, Damberg M, et al. (2005) Role of the serotonin transporter gene and family function in adolescent alcohol consumption. Alcoholism: Clinical and Experimental Research 29: 564–570.

Petzold AM, Balciunas D, Sivasubbu S, et al. (2009) Nicotine response genetics in the zebrafish. Proceedings of the National Academy of Sciences of the United States of America 106: 18662–18667.

Pietrzykowski AZ, Friesen RM, Martin GE, et al. (2008) Posttranscriptional regulation of BK channel splice variant stability by miR‐9 underlies neuroadaptation to alcohol. Neuron 59: 274–287.

Porjesz B, Begleiter H, Wang K, et al. (2002) Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes. Biological Psychology 61: 229–248.

Saccone SF, Hinrichs AL, Saccone NL, et al. (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics 16: 36–49.

Seneviratne C, Franklin J, Beckett K, et al. (2013) Association, interaction, and replication analysis of genes encoding serotonin transporter and 5‐HT3 receptor subunits A and B in alcohol dependence. Human Genetics 132: 1165–1176.

Sherva R, Wilhelmsen K, Pomerleau CS, et al. (2008) Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking. Addiction 103: 1544–1552.

Tsuang MT, Lyons MJ, Eisen SA, et al. (1996) Genetic influences on DSM‐III‐R drug abuse and dependence: a study of 3,372 twin pairs. American Journal of Medical Genetics 67: 473–477.

van der Zwaluw CS and Engels RC (2009) Gene–environment interactions and alcohol use and dependence: current status and future challenges. Addiction 104: 907–914.

Vrieze SI, Feng S, Miller MB, et al. (2014) Rare nonsynonymous exonic variants in addiction and behavioral disinhibition. Biological Psychiatry 75: 783–789.

Wang JC, Grucza R, Cruchaga C, et al. (2008) Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Molecular Psychiatry 14: 501–510.

Wang JC, Cruchaga C, Saccone NL, et al. (2009) Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Human Molecular Genetics 18: 3125–3135.

Wessel J, McDonald SM, Hinds DA, et al. (2010) Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerstrom test for nicotine dependence. Neuropsychopharmacology 35: 2392–2402.

WHO (2002) The World Health Report 2002. World Health Organization.

Xie P, Kranzler HR, Krauthammer M, et al. (2011) Rare nonsynonymous variants in alpha‐4 nicotinic acetylcholine receptor gene protect against nicotine dependence. Biological Psychiatry 70: 528–536.

Xie P, Kranzler HR, Krystal JH, et al. (2014) Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence. Addiction Biology 19: 955–964.

Yacubian J, Sommer T, Schroeder K, et al. (2007) Gene–gene interaction associated with neural reward sensitivity. Proceedings of the National Academy of Sciences of the United States of America 104: 8125–8130.

Yang Z, Seneviratne C, Wang S, et al. (2013) Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African‐American smokers. Drug and Alcohol Dependence 129: 217–225.

Yang J and Li MD (2014) Association and interaction analyses of 5‐HT3 receptor and serotonin transporter genes with alcohol, cocaine, and nicotine dependence using the SAGE data. Human Genetics 133: 905–918.

Yang J, Wang S, Yang Z, et al. (2015) The contribution of rare and common variants in 30 genes to risk nicotine dependence. Molecular Psychiatry 20: 1467–1478.

Yang J and Li MD (2016) Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions. Molecular Psychiatry 21: 992–1008.

Further Reading

Kreek MJ, Nielsen DA, Butelman ER and LaForge KS (2005) Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nature Neuroscience 8: 1450–1457.

Lerman C, LeSage MG, Perkins KA, et al. (2007) Translational research in medication development for nicotine dependence. Nature Reviews Drug Discovery 6: 746–762.

Lessov‐Schlaggar CN, Pergadia ML, Khroyan TV and Swan GE (2008) Genetics of nicotine dependence and pharmacotherapy. Biochemical Pharmacology 75: 178–195.

McCarthy MI, Abecasis GR, Cardon LR, et al. (2008) Genome‐wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics 9: 356–369.

Moffitt TE (2005) The new look of behavioral genetics in developmental psychopathology: gene–environment interplay in antisocial behaviors. Psychological Bulletin 131: 533–554.

Tsankova N, Renthal W, Kumar A and Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nature Reviews Neuroscience 8: 355–367.

Uhl GR, Drgon T, Johnson C, et al. (2008) Molecular genetics of addiction and related heritable phenotypes: genome‐wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects. Annals of the New York Academy of Sciences 1141: 318–381.

Wang J and Li MD (2010) Common and unique biological pathways associated with smoking initiation/progression, nicotine dependence, and smoking cessation. Neuropsychopharmacology 35: 702–719.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Yang, Zhongli, and Li, Ming D(Aug 2017) Molecular Genetics of Addictions. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022425.pub2]