Substance use disorders (SUD) are a major contributor to disability and disease burden worldwide. Risk for developing SUDs is influenced by variation in the genome. Identifying the genetic variants that influence SUD risk may help us to understand the biological mechanisms for the disorders and improve treatments. Genome-wide association studies (GWAS) have been successful in identifying many regions of the genome associated with common human disorders. Here, findings from recent GWAS of SUDs that involve illicit substances will be reviewed. Several GWAS have been reported, including studies on opioid and stimulant use disorder (cocaine and methamphetamine). Several of these GWAS report associations that are biologically interesting and statistically robust. Replication of the associations in independent samples and functional studies to understand the basis for the statistical associations will be important next steps.

1.
Degenhardt L, Whiteford HA, Ferrari AJ, Baxter AJ, Charlson FJ, Hall WD, Freedman G, Burstein R, Johns N, Engell RE, Flaxman A, Murray CJ, and Vos T: Global burden of disease attributable to illicit drug use and dependence: findings from the Global Burden of Disease Study 2010. Lancet 2013;382:1564-1574.
2.
McCabe SE, Teter CJ, Boyd CJ, Knight JR, Wechsler H: Nonmedical use of prescription opioids among U.S. college students: prevalence and correlates from a national survey. Addict Behav 2005;30:789-805.
3.
Degenhardt L, Chiu WT, Sampson N, Kessler RC, et al: Toward a global view of alcohol, tobacco, cannabis, and cocaine use: findings from the WHO World Mental Health Surveys. PLoS Med 2008;5:1053-1067.
4.
Degenhardt L, Hall W: Extent of illicit drug use and dependence, and their contribution to the global burden of disease. Lancet 2012;379:55-70.
5.
Diagnostic and Statistical Manual of Mental Disorders, ed 5. Washington, American Psychiatric Association, 2013.
6.
Kendler KS, Prescott CA: Cocaine use, abuse and dependence in a population-based sample of female twins. Br J Psychiatry 1998;173:345-350.
7.
Kendler KS, Jacobson KC, Prescott CA, Neale MC: 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 2003;160:687-695.
8.
Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N, Meyer JM, Toomey R, Faraone SV, Eaves L: Genetic influences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. Am J Med Genet 1996;67:473-477.
9.
Sklar P: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 (vol 43, pg 977, 2011). Nat Genet 2012;44:1072-1072.
10.
Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421-427.
11.
Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-976.
12.
Coffee, Caffeine Genetics Consortium, Cornelis MC, Byrne EM, Esko T, et al: Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Mol Psychiatry 2015;20:647-656.
13.
Gelernter J, Kranzler HR, Sherva R, Almasy L, Koesterer R, Smith AH, Anton R, Preuss UW, Ridinger M, Rujescu D, Wodarz N, Zill P, Zhao H, Farrer LA: Genome-wide association study of alcohol dependence: significant findings in African- and European-Americans including novel risk loci. Mol Psychiatry 2014;19:41-49.
14.
Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, et al: Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 2010;42:448-453.
15.
Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, et al: Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet 2010;6.
16.
Bierut LJ, Goate AM, Breslau N, Johnson EO, et al: ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Mol Psychiatry 2012;17:445-450.
17.
Frank J, Cichon S, Treutlein J, Ridinger M, et al: Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addict Biol 2012;17:171-180.
18.
Park BL, Kim JW, Cheong HS, Kim LH, Lee BC, Seo CH, Kang TC, Nam YW, Kim GB, Shin HD, Choi IG: Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication. Hum Genet 2013;132:657-668.
19.
Edenberg HJ: The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 2007;30:5-13.
20.
Liu JZ, Tozzi F, Waterworth DM, Pillai SG, et al: Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 2010;42:436-440.
21.
Tobacco and Genetics Consortium: Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 2010;42:441-447.
22.
Saccone SF, Hinrichs AL, Saccone NL, Chase GA, et al: Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 2007;16:36-49.
23.
Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ: Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature 2011;471:597-601.
24.
Frahm S, Slimak MA, Ferrarese L, Santos-Torres J, Antolin-Fontes B, Auer S, Filkin S, Pons S, Fontaine JF, Tsetlin V, Maskos U, Ibanez-Tallon I: Aversion to nicotine is regulated by the balanced activity of beta4 and alpha5 nicotinic receptor subunits in the medial habenula. Neuron 2011;70:522-535.
25.
Jackson KJ, Marks MJ, Vann RE, Chen X, Gamage TF, Warner JA, Damaj MI: Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice. J Pharmacol Exp Ther 2010;334:137-146.
26.
Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, et al: Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 2008;165:1163-1171.
27.
Kuryatov A, Berrettini W, Lindstrom J: Acetylcholine receptor (AChR) alpha5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (alpha4beta2)(2)alpha5 AChR function. Mol Pharmacol 2011;79:119-125.
28.
Jensen KP, DeVito EE, Herman AI, Valentine GW, Gelernter J, Sofuoglu M: A CHRNA5 smoking risk variant decreases the aversive effects of nicotine in humans. Neuropsychopharmacology 2015;40:2813-2821.
29.
Gelernter J, Kranzler HR, Sherva R, Koesterer R, Almasy L, Zhao H, Farrer LA: Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways. Biol Psychiatry 2014;76:66-74.
30.
Edenberg HJ: The collaborative study on the genetics of alcoholism: an update. Alcohol Res Health 2002;26:214-218.
31.
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;95:14-22.
32.
Bierut LJ: Genetic variation that contributes to nicotine dependence. Pharmacogenomics 2007;8:881-883.
33.
Bierut LJ, Agrawal A, Bucholz KK, Doheny KF, et al: A genome-wide association study of alcohol dependence. Proc Natl Acad Sci USA 2010;107:5082-5087.
34.
Nelson EC, Agrawal A, Heath AC, Bogdan R, et al: Evidence of CNIH3 involvement in opioid dependence. Mol Psychiatry DOI: 10.1038/mp.2015.102.
35.
Li D, Zhao H, Kranzler HR, Li MD, Jensen KP, Zayats T, Farrer LA, Gelernter J: Genome-wide association study of copy number variations (CNVs) with opioid dependence. Neuropsychopharmacology 2015;40:1016-1026.
36.
Manolio TA, Collins FS, Cox NJ, Goldstein DB, et al: Finding the missing heritability of complex diseases. Nature 2009;461:747-753.
37.
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M: Penn CNV: An integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007;17:1665-1674.
38.
Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P, Bassett AS, Seller A, Holmes CC, Ragoussis J: QuantiSNP: an objective Bayes Hidden-Markov model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res 2007;35:2013-2025.
39.
Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, et al: Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011;70:863-885.
40.
Zhou X, Wang L, Hasegawa H, Amin P, Han BX, Kaneko S, He Y, Wang F: Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proc Natl Acad Sci USA 2010;107:9424-9429.
41.
Glessner JT, Reilly MP, Kim CE, Takahashi N, et al: Strong synaptic transmission impact by copy number variations in schizophrenia. Proc Natl Acad Sci USA 2010;107:10584-10589.
42.
Stopkova P, Saito T, Papolos DF, Vevera J, Paclt I, Zukov I, Bersson YB, Margolis BA, Strous RD, Lachman HM: Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia. Biol Psychiatry 2004;55:981-988.
43.
Grucza RA, Johnson EO, Krueger RF, Breslau N, Saccone NL, Chen LS, Derringer J, Agrawal A, Lynskey M, Bierut LJ: Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. Addict Biol 2010;15:346-357.
44.
Nishizawa D, Fukuda K, Kasai S, Hasegawa J, et al: Genome-wide association study identifies a potent locus associated with human opioid sensitivity. Mol Psychiatry 2014;19:55-62.
45.
Yan Z, Feng J, Fienberg AA, Greengard P: D-2 dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons. Proc Natl Acad Sci USA 1999;96:11607-11612.
46.
McClung CA, Nestler EJ: Regulation of gene expression and cocaine reward by CREB and Delta FosB. Nat Neurosci 2003;6:1208-1215.
47.
Carlezon WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ: Regulation of cocaine reward by CREB. Science 1998;282:2272-2275.
48.
Nielsen DA, Ji F, Yuferov V, Ho A, He CS, Ott J, Kreek MJ: Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction. Psychiatr Genet 2010;20:207-214.
49.
Gelernter J, Sherva R, Koesterer R, Almasy L, Zhao H, Kranzler HR, Farrer L: Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene. Mol Psychiatry 2014;19:717-723.
50.
Gelernter J, Panhuysen C, Weiss R, Brady K, Hesselbrock V, Rounsaville B, Poling J, Wilcox M, Farrer L, Kranzler HR: Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia. Am J Med Genet B Neuropsychiatr Genet 2005;136B:45-52.
51.
Thermes V, Candal E, Alunni A, Serin G, Bourrat F, Joly JS: Medaka simplet (FAM53B) belongs to a family of novel vertebrate genes controlling cell proliferation. Development 2006;133:1881-1890.
52.
Aoki M, Segawa H, Naito M, Okamoto H: Identification of possible downstream genes required for the extension of peripheral axons in primary sensory neurons. Biochem Biophys Res Commun 2014;445:357-362.
53.
Dickson PE, Miller MM, Calton MA, Bubier JA, Cook MN, Goldowitz D, Chesler EJ, Mittleman G: Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel. Psychopharmacology (Berl) 2016;233:701-714.
54.
Uhl GR, Drgon T, Liu QR, Johnson C, Walther D, Komiyama T, Harano M, Sekine Y, Inada T, Ozaki N, Iyo M, Iwata N, Yamada M, Sora I, Chen CK, Liu HC, Ujike H, Lin SK: Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry 2008;65:345-355.
55.
Hart AB, Engelhardt BE, Wardle MC, Sokoloff G, Stephens M, de Wit H, Palmer AA: Genome-wide association study of d-amphetamine response in healthy volunteers identifies putative associations, including cadherin 13 (CDH13). PLoS One 2012;7:e42646.
56.
Brady KT, Lydiard RB, Malcolm R, Ballenger JC: Cocaine-induced psychosis. J Clin Psychiatry 1991;52:509-512.
57.
Ikeda M, Okahisa Y, Aleksic B, Won M, Kondo N, Naruse N, Aoyama-Uehara K, Sora I, Iyo M, Hashimoto R, Kawamura Y, Nishida N, Miyagawa T, Takeda M, Sasaki T, Tokunaga K, Ozaki N, Ujike H, Iwata N: Evidence for shared genetic risk between methamphetamine-induced psychosis and schizophrenia. Neuropsychopharmacology 2013;38:1864-1870.
58.
Ikeda M, Aleksic B, Kinoshita Y, Okochi T, et al: Genome-wide association study of schizophrenia in a Japanese population. Biol Psychiatry 2011;69:472-478.
59.
Wetherill L, Agrawal A, Kapoor M, Bertelsen S, et al: Association of substance dependence phenotypes in the COGA sample. Addict Biol 2015;20:617-627.
60.
Johnson EO, Hancock DB, Levy JL, Gaddis NC, Page GP, Glasheen C, Saccone NL, Bierut LJ, Kral AH: KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex. Addict Biol DOI: 10.1111/adb.12286.
61.
McGue M, Zhang Y, Miller MB, Basu S, Vrieze S, Hicks B, Malone S, Oetting WS, Iacono WG: A genome-wide association study of behavioral disinhibition. Behav Genet 2013;43:363-373.
62.
Vrieze SI, Feng S, Miller MB, Hicks BM, Pankratz N, Abecasis GR, Iacono WG, McGue M: Rare nonsynonymous exonic variants in addiction and behavioral disinhibition. Biol Psychiatry 2014;75:783-789.
63.
Hicks BM, Schalet BD, Malone SM, Iacono WG, McGue M: Psychometric and genetic architecture of substance use disorder and behavioral disinhibition measures for gene association studies. Behav Genet 2011;41:459-475.
64.
Purcell SM, Wray NR, Stone JL, Visscher PM, et al: Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748-752.
65.
Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, Degenhardt F, Nothen MM, Collier DA, Ripke S, Naber D, Rietschel M: Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry 2015;20:150-151.
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