Table 2.
Represents the GARS Polymorphisms and only positive case –control association and longitudinal studies
| Gene | Poly-morphism | Association | Case-Control | Reference |
|---|---|---|---|---|
| DRD1 | Rs4532 | Rs 4532 could predict decreased postopioid dependence pleasure. | The present study included N=425 unrelated opioid addicts registered in the Methadone Maintenance Treatment Program at Xi’an Mental Health Center of China. The OD diagnosis was established using DSM-IV criteria and based on medical record, urine test, and interview. The controls consisted of N=514 unrelated healthy persons who had never been diagnosed with substance abuse and mental illness. | Zhu F (2013) Dopamine D1 receptor gene variation modulates opioid dependence risk by affecting transition to addiction. PloS one 8: e70805. |
| Rs4532 | Statistically significant associations of polymorphisms in DRD1 rs4532 with alcoholism were found. | In another study N=140 male alcohol dependent subjects attending the outpatient department (OPD) at National Drug Dependence Treatment Centre, AIIMS, were screened. A total of N=122 unrelated healthy male employees of the hospital, without any history of substance use (except nicotine) were included as controls in the study. | Prasad P (2013). Case-control association analysis of dopamine receptor polymorphisms in alcohol dependence: a pilot study in Indian males. BMC research notes, 6, 418. doi:10.1186/1756-0500-6-418 | |
| Rs4532 | A specific haplotype rs686*T-rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample (p = 5 x 10(−6)). | A third study analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes | Batel P, Houchi H, Daoust M, Ramoz N, Naassila M, Gorwood P. A haplotype of the DRD1 gene is associated with alcohol dependence. Alcohol Clin Exp Res. 2008 Apr;32(4):567-72. doi: 10.1111/j.1530-0277.2008.00618.x. | |
| DRD2 | Rs1800497 | DRD2/ANKK1 TaqIA polymorphism was significantly associated with increased risk of opioid dependence under homo zygote, dominant, and recessive genetic model, respectively (homozygote: OR=1.546, 95%CI=1.279-1.87; dominant: OR=1.265, 95%CI=1.055-1.516; recessive: OR=1.409, 95%CI=1.182-1.680). | A total of 25 available case-control studies testing the association between the polymorphism and common illicit drug dependence were examined through Oct 2013. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were estimated using fixed- and random-effects models when appropriate. | Deng XD (2015) Association between DRD2/ANKK1 TaqIA polymorphism and common illicit drug dependence: evidence from a meta-analysis. Hum Immunol. 2015 Jan;76(1):42-51. doi:10.1016/j.humimm.2014.12.005. |
| Rs1800497 | TaqI A1 polymorphism was significantly increased for opioid dependence risk (homozygote comparison: OR, 2.06; 95% CI, 1.25-3.42; dominant comparison: OR, 1.34; 95% CI, 1.08-1.67). | A meta-analysis, including N=6,846 opioid dependence cases and N=4,187 controls from 22 individual studies | Chen D, Liu F, Shang Q, Song X, Miao X, Wang Z. Association between polymorphisms of DRD2 and DRD4 and opioid dependence: evidence from the current studies. Am J Med Genet B Neuropsychiatr Genet. 2011 ;156B(6):661-70. doi: 10.1002/ajmg.b.31208. | |
| Rs1800497 | rs1800497 was significantly associated in men with excessive alcohol consumption. | The study sample (N = 1533, of which 746 were women) consisted of 653 heavy consumers and N= 880 very low consumers from the Spanish sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. | Celorrio D, Munoz X, Amiano P, Dorronsoro M, Bujanda L, Sánchez MJ, Molina-Montes E, Navarro C, Chirlaque MD, MariaHuerta J, Ardanaz E, Barricarte A, Rodriguez L, Duell EJ, Hijona E· Herreros-Villanueva M,· Sala N Alfonso-Sanchez MA,de Pancorbo MM. Influence of Dopaminergic System Genetic bâriation and Lifestyle Factors on Excessive Alcohol Consumption. Alcohol Alcohol. 2016 May;51 (3):258-67. doi: 10.1093/alcalc/agv114. | |
| Rs1800497 | Genetic variation in rs1800497 play an equal role in predicting alcohol drinking two years later and are most important in predicting the increase in alcohol consumption | Examined N= 736 adolescents from the IMAGEN longitudinal study for alcohol drinking during early (mean age= 14.37) and again later (mean age=16.45) adolescence. | Heinrich A, IMAGEN consortium. Prediction of alcohol drinking in adolescents: Personality-traits, behavior, brain responses, and genetic variations in the context of reward sensitivity. Biol Psychol. 2016 ;118:79-87. doi: 10.1016/j.biopsycho.2016.05.002. | |
| Rs1800497 | Rs1800497 genotype distribution is significantly associated to Alcohol Dependence (O.R.=1.551, p=0.023), with A1 * allele displaying an O.R.=1.403 (p=0.029). | The study design was a case-control. In total, N=−280 alcoholic subjects (213 men and 67 woman) and N=280 age- and sex-matched control subjects were recruited for this study | Vlignini F, Napolioni V, Codazzo C, Carpi FM, Vitali M, Romeo M, Ceccanti M. DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: association and gene-gene interaction study in a population of Central Italy. Neurosci Lett. 2012;;522(2):103-7. doi: 10.1016/j.neulet.2012.06.008. | |
| Rs1800497 | Homozygous genotype variants (A1A11 A2A2) were over-represented in case groups compared to controls, while heterozygotes were more frequently observed in control group, but no statistically significant difference was found. Analysis of genotype A1A1 frequency showed 6% and 2% in case and control groups respectively. Statistical analysis pointed statistically significant overrepresentation of A1A1 genotype in case group, as opposed to expected –normal distribution with controls (OR=1.532 (CI=1.001-2.344) i p<0.05. This implies that A1A1 carriers have 1.5 fold increased risk for development of heroin addiction with 30-40% lower D2 receptors | 100 patients on Metadone Maintenance Treatment (MMT) and 100 age and sex matched healthy volunteers | Mehić-Basara, N, Oruč, L, Kapur-Pojskić, L, Ramić, J. (2013). Association of dopamine receptor gene polymorphism and psychological personality traits in liability for opioid addiction. Bosnian journal of basic medical sciences, 13(3), 158-162. doi: 10.17305/bjbms.2013.2355 | |
| Rs1800497 | In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence | 303 heroin dependent subjects and 555 healthy controls were genotyped for Rs1800497 and TaqIB (rs1079597) | Vereczkei A, Demetrovics Z, Szekely A, Sarkozy P, Antal P, Szilagyi A, Sasvari-Szekely M, Barta C. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence. PLoS One. 2013 Jun 28;8(6):e66592. doi: 10.1371/joumal.pone.0066592. PubMed PMID: 23840506; PubMed Central PMCID: PMC3696122. | |
| Rs1800497 | A random/fixed-effects meta-analyses using allelic contrasts found that the TaqIA (Rs1800497) significantly associated with addiction at < 0.0001 | A meta-analytic comparison of single marker analysis of the TaqIA (rs1800497) ,whereas A2 was compared to A1 in 6312 Cases vs. 7424 Controls in 20 independent studies | Li CY, Zhou WZ, Zhang PW, Johnson C, Wei L, Uhl GR. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction. BMC Genomics. 2011 Oct 15; 12:508. doi: 10.1186/1471-2164-12-508. PubMed PMID: 21999673; PubMed Central PMCID: PMC3215751. | |
| Rs1800497 | Meta-analysis demonstrated both allelic and genotypic association between the TaqIA polymorphism and AD susceptibility [allelic: P(Z)=1.1×10−5, OR=1.19; genotypic: P(Z)=3.2×10−5, OR=1.24]. The association remained significant after adjustment for publication bias using the trim and fill method | A large-scale meta-analysis to confirm the association between the TaqIA polymorphism and the risk for AD in over 18,000 subjects included in 61 case-control studies that were published up to August 2012 | Wang F, Simen A, Arias A, Lu QW, Zhang H. A large-scale meta-analysis of the association between the ANKK1/DRD2 TaqIA polymorphism and alcohol dependence. Hum Genet. 2013 Mar; 132(3):347-58. doi: 10.1007/s00439-012-1251-6. Epub 2012 Dec 1. PubMed PMID: 23203481; PubMed Central PMCID: PMC3570676. | |
| DRD3 | DRD3 Ser9Gly polymorphism (rs6280) | Linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e. increased reward-related DA release) in the middle caudate (r2 explained=0.24, β-weight=0.5, t=3.3, p = 0.003) and the ventral striatum | Twenty-six right-handed HCs (15 women; mean age 34.4±8.3) and 10 currently depressed, unmedicated patients with MDD (8 women; mean age 38.2±11.3) participated in the study | Savitz J, Hodgkinson CA, Mlartin-Soelch C, et al, The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement. PLoS one, 8:e54108, (2013). |
| rs6280 | This SNP was significantly associated with both AD overall (χ(2) = 10.09 and p = 0.001, and χ(2) = 10.60 and p = 0.005, for the recessive and additive models, respectively) and with Lesch type I AD (χ(2) = 11.70 and p = 0.001, and χ(2) = 11.70 and p = 0.003, for the recessive and additive models, respectively). The findings of this study suggest that the DRD3 rs6280 polymorphism is associated with the development of both AD overall and Lesch type I AD | The DRD3 rs6280 SNP was genotyped in a case-control sample comprising 245 AD patients and 130 healthy controls (HCs). Alcohol Use Disorders Identification Test (AUDIT) scores were also compared relative to genotype in all of the participants. | Kang SG, Lee BH, Lee JS, Chai YG, Ko KP, Lee HJ, Han DMI, Ji H, Jang GH, Shin HE. DRD3 gene rs6280 polymorphism may be associated with alcohol dependence overall and with Lesch type I alcohol dependence in Koreans. Neuropsychobiology. 2014;69(3):140-6. doi: 10.1159/000358062. | |
| rs6280 | The rs6280 and rs9825563 variants showed association with the development of early-onset heroin dependence. Authors suggest DRD3 is possibly a genetic factor in the development of early-onset heroin dependence | Eight polymorphisms in DRD3 were analyzed in 1067 unrelated Han Chinese subjects (N=566 heroin dependence patients and N= 501 controls). All participants were screened using the same assessment tool and all patients met the criteria for heroin dependence | Kuo SC, Yeh YW, Chen CY, Huang CC, Chang HA, Yen CH, Ho PS, Liang CS, Chou HW, Lu RB, Huang SY. DRD3 variation associates with early-onset heroin dependence, but not specific personality traits. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jun 3;51 :l-8. doi: 10.1016/j.pnpbp.2013.12.018. | |
| rs6280 | ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total amphetamine dependence patients (p = 0.0003 after 10,000 permutations). | A total of 1060 unrelated Han Chinese subjects (N=559 AD patients and N=501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. | Kuo SC, Yeh YW, Chen CY, Huang CC, Chen TY, Yen CH, Liang CS, Ho PS, Lu RB, Huang S Y. Novelty seeking mediates the effect of DRD3 variation on onset age of amphetamine dependence in Han Chinese population. Eur Arch Psychiatry Clin Neurosci. 2018 Apr;268(3):249-260. doi: 10.1007/s00406-016-0754-x. | |
| Single-marker analyses provided nominally significant evidence for associations of rs6280 in both heroin and cocaine addiction. | This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of N= 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). | Levran O, Randesi MI, da Rosa JC, Ott J, Rotrosen J, Adelson MI, Kreek MIJ. Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans. Ann Hum Genet. 2015 May;79(3):188-98. doi: 10.1111/ahg.12104. Epub 2015 Feb 27. PubMed PMID: 25875614; PubMed Central PMCID: PMC4399004. | ||
| DRD4 | Rs180095 48bP repeat VNTR | 521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele for heroin dependence | N-303 heroin dependent subjects and N=555 healthy controls were genotyped for Rs1800955, rs936462 and rs747302 of the DRD4 gene. | Vereczkei A, Demetrovics Z, Szekely A, Sarkozy P, Antal P, Szilagyi A, Sasvari-Szekely M, Barta C. Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence. PLoS One. 2013 Jun 28;8(6):e66592. doi: 10.1371/joumal.pone.0066592. PubMed PMID: 23840506; PubMed Central PMCID: PMC3696122. |
| The DRD4 polymorphism 120 bp tandem duplication, located 1.2 kb upstream of the initiation codon was analyzed. Statistically significant associations of polymorphisms in in DRD4 with alcoholism were found. | A total of 90 cases (alcohol dependent males) and 122 age and ethnicity matched healthy male controls were recruited in the study by following DSM-IV criteria. | Prasad P, Ambekar A, Vaswani M. Case-control association analysis of dopamine receptor polymorphisms in alcohol dependence: a pilot study in Indian males. BMC Res Notes. 2013 Oct 17;6:418. doi: 10.1186/1756-0500-6-418. PubMed PMID: 24135011; PubMed Central PMCID: PMC3 853477. | ||
| Rs180095 | The purpose of this longitudinal study was to investigate a genetic moderation effect of dopamine receptor-4 gene (DRD4) alleles that have 7 or more repeats on the efficacy of a preventive intervention to deter rural African American adolescents’ substance abuse In the so called control group the AA that carried at least one copy of the DRD4 7 repeat initiated drinking, behavior as a risk. | Adolescents (N = 502, M age = 16 years) were assigned randomly to the Strong African American Families–Teen (SAAF-T) program or to a control condition and were followed for 22 months. | Brody GH, Chen YF, Beach SR, Kogan SM, Yu T, Diclemente RJ, Wingood GM, Windle M, Philibert RA. Differential sensitivity to prevention programming: a dopaminergic polymorphism-enhanced prevention effect on protective parenting and adolescent substance use. Health Psychol. 2014 Feb;33(2):182-91. doi: 10.1037/a0031253. Epub 2013 Feb 4. PubMed PMID: 23379386; PubMed Central PMCID: PMC3695005. | |
| A random/fixed-effects meta-analyses using allelic contrasts found that the DRD4 48 BP repeat λ/NTR associated with addiction at < 0.06) | A meta-analytic comparison of single marker analysis of the DRD4 48 BP repeat VNTR was compared 2324 cases vs. 1932 controls in 6 independent studies | Li CY, Zhou WZ, Zhang PW, Johnson C, Wei L, Uhl GR. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction. BMC Genomics. 2011 Oct 15; 12:508. doi: 10.1186/1471-2164-12-508. PubMed PMID: 21999673; PubMed Central PMCID: PMC3215751. | ||
| Rs180095 | This longitudinal study found Alcohol use at age 33 was predicted by previous friends’ alcohol use and correlated with current friends’ alcohol use only for carriers of the DRD4 long allele. The long allele of DRD4 is associated with increased susceptibility to peer influences on alcohol use in young adulthood | Participants (N=340; 59% female; 98% White) reported on their own and their friends’ alcohol use at four time points between mean ages 17 and 33. Multigroup modeling tested differences in model paths and covariances across high vs. low risk DRD4 polymorphisms. | Mrug S, Windle M. DRD4 and susceptibility to peer influence on alcohol use from adolescence to adulthood. Drug Alcohol Depend. 2014 Dec 1; 145:168-73. doi: 10.1016/j.drugalcdep.2014.10.009. Epub 2014 Oct 23. PubMed PMID: 25457740; PubMed Central PMCID: PMC4268151. | |
| Rs180095 | In this study N=50 carried DRD4 7R and N=91 did not carry the DRD4 7 R. A significant gene-by-environment interaction suggested that the same-day association between witnessing substance use and antisocial behavior was significantly stronger among adolescents with, versus without, with the DRD4-7R allele. Providing evidence for risk for SUD. | Young adolescents (N=151) at heightened risk for both exposure to substance use. Adolescents were, on average, 13 years of age. DRD4 genotype was determined. They split adolescents into two groups: (1) those who possessed at least one copy of the 7R allele on either chromosome versus (2) those who did not possess a copy of the 7R allele on either chromosome. | Russell MA, Wang L, Odgers CL. Witnessing substance use increases same-day antisocial behavior among at-risk adolescents: Gene-environment interaction in a 30-day ecological momentary assessment study. Dev Psychopathol. 2016 Nov;28(4pt2):1441-1456. doi: 10.1017/S0954579415001182. Epub 2015 Dec 9. PubMed PMID: 26648004; PubMed Central PMCID: PMC5330259. | |
| Rs180095 | DRD4 7R more commonly found in individuals with high quantity/frequency of drug use compared with controls | The DRD4 48 BP repeat (7R) was evaluated in 184 substance abusers and 122 controls | Vandenbergh DJ,Rodriguez LA,Hivert E,Schiller JH,Villareal G,Pugh EW,Lachman H,Uhl GR. Long forms of the dopamine receptor (DRD4) gene VNTR are more prevalent in substance abusers: no interaction with functional alleles of the catechol-o-methyltransferase (COMT) gene. Am J Med Genet. 2000 Oct 9;96(5):678-83. | |
| Rs180095 | DSM IV methamphetamine disorders was assessed in each subject. 7-repeat allele more commonly found in methamphetamine abusers than controls | N=416 methamphetamine users and N=435 controls genotyped for presence vs. absence of 7- repeat allele | Chen CK,Hu X,Lin SK,Sham PC,Loh el-W,Li T,Murray RM.Ball DM. Association analysis of dopamine D2-like receptor genes and methamphetamine abuse. Psychiatr Genet. 2004 Dec;14(4):223-6. | |
| Using individual alleles and grouping 5-7 repeats as “long” | Association of 7-repeat allele and alcohol dependence in case control design | Case control design-218 cases and 197 controls, −76 alcoholics and their parents | Franke P, Wang T, Nothen MM, Knapp M, Neith H, Lichtermann D, Meyer Zur Caprllen K, Sander T, Propping P, Maier W. DRD4 exon III VNTR polymorphism: a case-control and family-based association approach. Addiction Biology. 2000 Jan;5(1):289–95. | |
| Rs180095 | DSM-IV opioid dependence. Association of 7-repeat allele and opioid dependence | 141 opioid dependent patients and 110 controls | Kotler M, Cohen H, Segman R, Gritsenko I, Nemanov L, Lerer B, Kramer I, Zer-Zion M, Kletz I, Ebstein RP. Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects. Mol Psychiatry. 1997 May;2(3):251–4. | |
| DRD4 haplotype (including exon 3 VNTR) | Association of DRD4 haplotype (including exon 3 VNTR) with methamphetamine abuse and interaction of exon 3 VNTR with COMT 158 Val/Met polymorphism | 228 methamphetamine abusers and 181 controls | Li T, Chen CK, Hu X, Ball D, Lin SK, Chen W, Sham PC, Loh el-W, Murray RM, Collier DA. Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):120–4. | |
| DRD4 5 repeat allele | DSM-III-R alcohol dependence Increased frequency of DRD4 5 repeat allele in alcoholics with protective ALDH2 allele compared with controls on alcoholics without this protective | 655 Japanese alcoholics and 144 unrelated controls | Muramatsu T, Higuchi S, Murayama M, Matsushita S, Hayashida M. Association between alcoholism and the dopamine D4 receptor gene. J Med Genet. 1996 Feb;33(2):113–5. | |
| 4 repeat homozygotes compared with all others | DSM-IV alcohol dependence in parents. 4-repeat homozygotes less common in children of alcoholics | 18 children of alcoholics and 23 children of nonalcoholic parents | Namkoong K, Cheon KA, Kim JW, Jun JY, Lee JY. Association study of dopamine D2, D4 receptor gene, GABAA receptor beta subunit gene, serotonin transporter gene polymorphism with children of alcoholics in Korea: a preliminary study. Alcohol. 2008 Mar;42(2):77–81 | |
| Rs180095 48bP repeat VNTR | The long-repeat alleles of the DRD4 exon 3 VNTR polymorphism were found more frequently in the heroin addicts (P=0.019). | N=894 male heroin addicts without other psychiatric disorders, were recruited as subjects. Another community N=180 males were selected randomly as controls. | Chien CC, Lin CH, Chang YY, Lung FW. Association of VNTR polymorphisms in the MAOA promoter and DRD4 exon 3 with heroin dependence in male Chinese addicts. World J Biol Psychiatry. 2010 Mar;11(2 Pt2):409-16. doi: 10.3109/15622970903304459. | |
| DAT1 | base repeat VNTR | This analysis showed that the 6R6R genotype was associated with crack cocaine addiction (OR = 1.844; CI = 1.101-3.089; p = 0.020). | Compared allele and genotype frequencies of a 30-bp variable number of tandem repeats (VNTR) polymorphism of the DAT1 gene, located at intron 8, between adult crack cocaine users and non-addicted individuals. A cross-sectional sample of N=239 current adult crack abusers or dependents from in- and outpatient clinics and N= 211 control individuals was collected in Brazil. | Stolf AR, Muller D, Schuch JB, Akutagava-Martins GC, Guimaraes LSP, Szobot CM, Halpern R, Kessler FHP, Pechansky F, Roman T2. Association between the Intron 8 VNTR Polymorphism of the DAT1 Gene and Crack Cocaine Addiction. Neuropsychobiology. 2017;75(3):141-144. doi: 10.1159/000485128. |
| 9R allele compared to 10R. | Variants in DAT VNTR, showed that the presence of the 9-9 genotype significantly increases the risk of irritability and direct aggressiveness more than six and 10 times with respect to the 9-10 genotype in heroin addicts compared to controls. 9-repeat allele of the DAT polymorphism confers increased susceptibility to antisocial - violent behavior and aggressiveness in heroin addicts. | Polymorphism of a variable number of tandem repeats (VNTR) in the 3’ untranslated region of exon 15 of the SLC6A3 gene, coding for the dopamine transporter (DAT). The repeat number of the DAT polymorphism was assessed in N=125 healthy subjects and N= 104 heroin-dependent subjects (including 52 addicted individuals with violent behavior and criminal records | Gerra G, Garofano L, Pellegrini C, Bosari S, Zaimovic A, Moi G, Avanzini P, Talarico E, Gardini F, Donnini C. Allelic association of a dopamine transporter gene polymorphism with antisocial behaviour in heroin-dependent patients. Addict Biol. 2005 Sep;10(3):275-81. | |
| 9R allele compared to 10R | DAT1, genotype 9/9 was associated with early opiate addiction. | VNTR polymorphisms of the dopamine transporter (DAT1) gene were studied in Russian male opiate addicts. Number of addicts unknown | Galeeva AR, Gareeva AE, Iur’ev EB, Khusnutdinova EK. VNTR polymorphisms of the serotonin transporter and dopamine transporter genes in male opiate addicts. Mol Biol (Mosk). 2002 Jul-Aug;36(4):593-8. | |
| 9R allele compared to 10R | One 9R-allele of DAT1 (compared with homozygote carriers of the 10R-allele) show heightened reactivity to drug-related reinforcement in addiction in cocaine abusers compared to controls. Because drug cues contribute to relapse, our results identify the DAT1R 9R-allele as a vulnerability allele for relapse especially during early abstinence (e.g, detoxification). | 9R allele compared to 10R in N=73 human cocaine-addicted individuals and N=47 healthy controls, | Moeller SJ, ParvazMA, Shumay E, Beebe-Wang N, Konova AB, Alia-Klein N, Volkow ND, Goldstein RZ. Gene x abstinence effects on drug cue reactivity in addiction: multimodal evidence. J Neurosci. 2013 Jun 12;33(24):10027-36. doi: 10.1523/JNEUROSCI.0695-13.2013. PubMed PMID: 23761898; PubMed Central PMCID: PMC3682385. | |
| Repeat polymorphisms, including a 30-bp variable-number tandem repeat (VNTR) in intron 8 (Int8 VNTR) | Positive association was observed with allele 3 of the Int8 VNTR and cocaine abuse (allele odds ratio = 1.2, 95% confidence interval = 1.01-1.37, P = 0.036; 3/3 homozygote odds ratio = 1.45, 95% confidence interval = 1.18-1.78, P = 0.0008) The study demonstrates a robust association between cocaine dependence and a VNTR allele in SLC6A3, | Genotyped in cocaine-dependent abusers (N = 699) and in controls with no past history of drug abuse (N = 866) from Sao Paulo, Brazil. | Guindalini C, Howard M, Haddley K, Laranjeira R, Collier D, Ammar N, Craig I, O’Gara C, Bubb VJ, Greenwood T, Kelsoe J, Asherson P, Murray RM, Castelo A, Quinn JP, Vallada H, Breen G. A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample. Proc Natl Acad Sci USA. 2006 Mar 21 ;103(12):4552-7. doi: 10.1073/pnas.0504789103. Epub 2006 Mar 14. PubMed PMID: 16537431; PubMed Central PMCID: PMC1450209. | |
| VNTR polymorphism in the 3’ untranslated region of DAT1 | Found a significantly increased prevalence of the nine-repeat allele in alcoholics compared to controls and suggested that the 9R is a major genetic determinant of vulnerability to severe alcohol withdrawal symptoms. | Analyzed a VNTR polymorphism in the 3’ untranslated region of DAT1. In N= 93 alcoholics displaying withdrawal seizures or delirium, compared with N=93 ethnically matched nonalcoholic controls | Sander T, Harms H, Podschus J, Finckh U, Nickel B, Rolfs A, Rommelspacher H, Schmidt LG. Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium. Biol Psychiatry. 1997 Feb 1;41(3):299-304. | |
| 9R allele compared to 10R | Compared to the 10R the 9 allele was associated with a greater number of drinking days | Alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers. | Weerts EMI, Wand GS, Mlaher B, Xu X, Stephens MIA, Yang X, MIcCaul MCE. Independent and Interactive Effects of OPRMI1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers. Alcohol Clin Exp Res. 2017 Jun;41(6):1093-1104. doi: 10.1111/acer.13384. Epub 2017 Apr 26. PubMed PMID: 28376280; PubMed Central PMCID: PMC5483245. | |
| 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 16 copies in the 3’-untranslated region (UTR) of the gene | Alcoholism phenotype was defined based on the DSM-IV criteria. The DAT1 VNTR was significantly associated with alcoholism in Badaga population but not in Kota population. Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcoholism, but that these associations are population specific. | Genotyped the VNTR of DAT1 gene in a sample of N=206 subjects from the Kota population (111 alcohol dependence cases and 95 controls) and N=142 subjects from Badaga population (81 alcohol dependence cases and 61 controls). | Bhaskar LV, Thangaraj K, Wasnik S, Singh L, Raghavendra Rao V Dopamine transporter (DAT1) VNTR polymorphism and alcoholism in two culturally different populations of south India. Am J Addict. 2012 Jul-Aug;21(4):343-7. doi: 10.1111/j.1521-0391.2012.00244.x. | |
| 9R of DAT1; SLC6A3) to 10R. | The frequency of individuals carrying the allele A9 [f(A9+)] was significantly higher (P = 0.01) in the group of alcoholics [f(A9+) = 0.48] compared with healthy controls [f(A9+) = 0.32].Authors suggest the allele A9 is strongly associated with alcoholism | A group of N=102 healthy subjects and = 216 alcoholics | Kohnke MD, Batra A, Kolb W, Kohnke AMI, Lutz U, Schick S, Gaertner I Association of the dopamine transporter gene with alcoholism. Alcohol Alcohol. 2005 Sep-Oct;40(5):339-42. | |
| Association between the 9-repeat allele (A9) of a 40-bp variable number tandem repeat (VNTR) polymorphism in the 3’ untranslated region (31 UTR) of the SLC6A3 gene and alcoholism. | Significant associations were observed between SLC6A3 VNTR A9 and alcoholics with AWS or DT at the genotypic as well as allelic level when all ethnic populations or only Caucasian populations were considered (p< 0.05, OR 1.5-2.1). | Meta-analyses were performed for population-based case-control association studies of the SLC6A3 VNTR polymorphism with Mexican-Americans alcoholism including N=337 controls and N= 365 alcoholics | Du Y, Nie Y, Li Y, Wan YJ. The association between the SLC6A3 VNTR 9-repeat allele and alcoholism-a meta-analysis. Alcohol Clin Exp Res. 2011 Sep;35(9):1625-34. doi: 10.1111/j.1530-0277.2011.01509.x. Epub 2011 May 9. PubMed PMID: 21554332; PubMed Central PMCID: PMC4084904. | |
| A meta –analysis association of 3’-untranslated region variable-number tandem repeat (VNTR) polymorphism in SLC6A3 with alcohol dependence (AD) | Significant association of VNTR A9 genotypes with AD in all ethnic populations (pooled odds ratio [OR] 1.12; 95% confidence interval [CI] 1.00, 1.25; p = 0.045) and the Caucasian population (pooled OR 1.15; 95% CI 1.01, 1.31; p = 0.036). The authors also found VNTR A9 genotypes to be significantly associated with alcoholism as defined by the DSM-IV criteria (pooled OR 1.18; 95% CI 1.03, 1.36; p = 0.02). The authors concluded that the VNTR polymorphism has an important role in the etiology of AD, and individuals with at least 1 A9 allele are more likely to be dependent on alcohol than persons carrying the non-A9 allele | Integrating 17 reported studies with 5,929 participants including N=3,280 alcoholics and N=2,649 controls | Ma Y, Fan R, Li MD. Meta-Analysis Reveals Significant Association of the 3’-UTR VNTR in SLC6A3 with Alcohol Dependence. Alcohol Clin Exp Res. 2016 Jul;40(7):1443-53. doi: 10.1111/acer.13104. Epub 2016 May 24. Erratum in: Alcohol Clin Exp Res. 2017 Sep;41(9):1656-1659. PubMed PMID: 27219321; PubMed Central PMCID: PMC4930400. | |
| COMT | Rs4680 Catechol-O-methyl-transferase (COMT) Val158Met | Substance-use disorder, defined by DSM-IV criteria, was associated with the Val allele for Asian samples | A total of 363 datasets were included, consisting of N=56,998 cases and N=74,668 healthy controls from case control studies, and 2,547 trios from family based studies. A meta –analysis involving 15 psychiatric disorders. | Taylor S. Association between COV1T Val158Met and psychiatric disorders: A comprehensive meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2018 Mar;177(2):199-210. doi: 10.1002/ajmg.b.32556 |
| COMT rs4680 (Val158Met), | COMT rs4680 (Val158Met), patients with the Val/Val genotype showed the greatest pain variability and also experienced the greatest increase in pain as a result of physical activity. These results implicate that carriers of the COMT Val will consume more opioids to reduce their exacerbated pain. | A total of 120 knee OA patients reported on their pain 3 times per day over 22 days using handheld computers, and wore an accelerometer to capture daily physical activity | Martire LM, Wilson SJ, Small BJ, Conley YP, Janicki PK, Sliwinski MJ. COMT and OPRM1 Genotype Associations with Daily Knee Pain Variability and Activity Induced Pain. Scand J Pain. 2016 Jan 1;10:6-12. PubMed PMID: 26322144; PubMed Central PMCID: PMC4548933. | |
| Rs4680 Catechol-O-methyl-transferase (COMT) Val158Met | Linear regression of COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). | Analyzed Rs4680 SNP in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. | De Gregori M, Diatchenko L, Ingelmo PM, Napolioni V, Klepstad P, Belfer I, Molinaro V, Garbin G, Ranzani GN, Alberio G, Normanno M, Lovisari Somaini M, Govoni S, Mura E, Bugada D, Niebel T, Zorzetto M, De Gregori S, Molinaro M, Fanelli Allegri M. Human Genetic Variability Contributes to Postoperative Morphine Consumption. J Pain. 2016 May;17(5):628-36. doi: 10.1016/j.jpain.2016.02.003. | |
| Rs4680 Catechol-O-methyl-transferase (COMT) Val158Met | The COMT rs4680 gene variants were different between relapse and abstinent groups. The study demonstrated that the Val increases heroin relapse. | Evaluated COMT gene polymorphism (rs4680) on relapse to heroin use during 5-year follow up. 564 heroin dependent patients were enrolled in compulsory drug rehabilitation center | Su H, Li Z, Du J, Jiang H, Chen Z, Sun H, Zhao M. Predictors of heroin relapse: Personality traits, impulsivity, COV1T gene Val158met polymorphism in a 5-year prospective study in Shanghai, China. Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):712-9. doi: 10.1002/ajmg.b.32376 | |
| Rs4680 Catechol-O-methyl-transferase (COMT) Val158Met | The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level. While there was significance at the allelic level a better control could have resulted in a stronger association. | The control group consisted of N=250 unrelated Caucasians (102 female and 148 male) with a mean age of 36.8 years (s.d. ±12.8 years). The control group consisted of volunteers from the general public, hospital nursing and medical staff, and university staff and students. Formal screening for psychological disorders was not undertaken in the control population. As such the controls represent an unselected control group and may include individuals with substance dependence. This represents a poorly screened control N= 120 unrelated Caucasian participants (50 female and 70 male) diagnosed as opiate-dependent were recruited for this study. All subjects were assessed using a checklist of specific criteria by a consultant psychiatrist or physician experienced in drug and alcohol dependence and met DSM-IV criteria for opiate dependence. | Voisey J, Swagell CD, Hughes IP, Lawford BR, Young RM, Morris CP. A novel SNP in COV1T is associated with alcohol dependence but not opiate or nicotine dependence: a case control study. Behav Brain Funct. 2011 Dec 31;7:51. doi: 10.1186/1744-9081-7-51. PubMed PMID: 22208661; PubMed Central PMCID: PMC3268714. | |
| Catechol-O-methyltransferase (COMT) functional polymorphism, Val158Met | In women, the COMT Val158 allele frequency was maximal in alcoholic smokers (0.85), decreasing to 0.74 in nonalcoholic smokers, 0.67 in alcoholic nonsmokers, and 0.64 in nonalcoholic nonsmokers (chi2 = 11.1, 3 df, p = 0.011). Women showed a main effect of Val 158 on smoking (p=0.003). Both male and female alcoholics were more likely to have at least 1 Vail58 allele compared with nonalcoholics (0.95 vs 0.88, p < 0.05). Approximately 30% of all participants were long-term, non-addicted light, social smokers (3.6+/−1.7 cigarettes/d); they had the same Vail 58Viet frequencies as non-smokers. | The aims of our study were firstly to investigate patterns of alcohol and tobacco consumption and comorbidity between alcoholism and smoking in Plains American Indians. Diagnostic and Statistical Manual-III-R lifetime diagnoses were assigned to 342 community-ascertained Plains American Indians (201 women, 141 men). | Enoch MA, Waheed JF, Harris CR, Albaugh B, Goldman D. Sex differences in the influence of COMT Val158Met on alcoholism and smoking in plains American Indians. Alcohol Clin Exp Res. 2006 Mar;30(3):399-406. | |
| A functional polymorphism (COMTVal158Met) | There was a difference in genotype frequencies between cannabis users and controls, including the distribution of the COMT genotypes (Val/Val, Val/Met) (P < 0.001) and alleles (Val vs , Met) (P< 0.01), | N=55 cannabis users and N= 75 normal controls were enrolled in this study | Baransel Isir AB, Oguzkan S, Nacak M, Gorucu S, Dulger HE, Ars1an A. The catechol-O-methyl transferase Val158Met polymorphism and susceptibility to cannabis dependence. Am J Forensic Med Pathol. 2008 Dec;29(4):320-2. doi: 10.1097/PAF.0b013e3181847e56. | |
| COMT Val158Met | Substance users and normal controls significantly differed in allele frequencies of COMT Val158Met (p = 0.039) | 187 substance users and 386 normal controls were recruited from Northern Taiwan. | Chen CK, Lin SK, Chiang SC, Su LW, Wang LJ. Polymorphisms of COMT Val158Met and DAT1 3’-UTR VNTR in illicit drug use and drug-related psychiatric disorders. Subst Use Misuse. 2014 Sep;49(11):1385-91. doi: 10.3109/10826084.2014.901391. | |
| COMT 158 Val/Met | The authors found a significant excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse | A case/control design with N=416 methamphetamine abusing subjects and N= 435 normal controls. | Li T, Chen CK, Hu X, Ball D, Lin SK, Chen W, Sham PC, Loh el-W, Murray RM, Collier DA. Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):120-4. | |
| COMT 158 Val/Met | COMT Val158Met may affect the intermediate phenotype of central dopamine receptor sensitivity. COMTVall 58Viet may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain | Patients (n = 110) were alcohol dependent whereas controls (n = 99) were recruited through advertisements in regional newspapers. | Schellekens AF, Franke B, Ellenbroek B, Cools A, de Jong CA, Buitelaar JK, Verkes RJ. Reduced dopamine receptor sensitivity as an intermediate phenotype in alcohol dependence and the role of the COMT Val158Met and DRD2 Taql A genotypes. Arch Gen Psychiatry. 2012 Apr;69(4):339-48. doi: 10.1001/archgenpsychiatry.2011.1335. | |
| Val158Met polymorphism of the COMT gene | Found a relationship between the Val158Met polymorphism of the COMT gene and alcoholism in male subjects. Found the significant difference between male alcoholics and male controls in allele and genotype frequencies (p<0,007; and p<0,04 respectively). Confirmed the relationship between the COMT polymorphism and alcoholism in the Czech male population. | Case control study we analyzed DNA samples from N=799 subjects in total (279 male alcoholics and 120 female alcoholics, 151 male controls and 249 female controls). | Serý O, Didden W, Mikes V, Pitelová R, Znojil V, Zvolský P. The association between high-activity COMT allele and alcoholism. Neuro Endocrinol Lett. 2006 Feb-Apr;27(1-2):231-5. | |
| OPRM1 | A118G(rs1799971) polymorphism | Meta-analysis showed significant association between this polymorphism and susceptibility to opioid dependence in overall studies | Thirteen studies (n = 9385), comprising 4601 opioid dependents and 4784 controls | Haerian BS, Haerian MS. OPRM1 rs 1799971 polymorphism and opioid dependence: evidence from a meta-analysis. Pharmacogenomics. 2013 May;14(7):813-24. doi: 10.2217/pgs.13.57. |
| OPRMI (rs1799971) | Individuals homozygous for AA at the OPRMI (rs 1799971) polymorphisms required less postsurgical opioid compared with those homozygous for GG (Hedges g, −0.270; 95% confidence interval, −0.433 to −0.108; P=0.001. Implicating more opioids required with G risk allele. | Fifty-one studies included in meta- analysis | Choi SW, Lam DMH, Wong SSC, Shiu HHC, Wang AXM, Cheung CW. Effects of Single Nucleotide Polymorphisms on Surgical and Postsurgical Opioid Requirements: A Systematic Review and Meta-Analysis. Clin J Pain. 2017 Dec;33(12):1117-1130. doi: 10.1097/AJP.0000000000000498. | |
| OPRMI (rs 1799971) | Ethnicity-specific meta-analyses revealed that the A118G polymorphism was significantly associated with alcohol dependence risk in Asians (GA vs. AA: odds ratio [OR], 1.73; 95% confidence interval [CI], 1.33-2.25; GA+GG vs. AA: OR, 1.57; 95% CI, 1.22-2.02), but not in Caucasians (GAvs. AA: OR, 1.05; 95% CI, 0.75-1.49; GA+GG vs. AA: OR, 1.11; 95% CI, 0.79-1.55). The OPRMI A118G polymorphism may contribute to the susceptibility of alcohol dependence in Asians | Twelve independent studies with N= 1900 cases and N=2382 controls were included. Five studies were conducted in Asians and seven in Caucasians | Chen D, Liu L, Xiao Y, Peng Y, Yang C, Wang Z. Ethnic-specific meta-analyses of association between the OPRMI A118G polymorphism and alcohol dependence among Asians and Caucasians. Drug Alcohol Depend. 2012 Jun 1;123(1-3):1-6. doi: 10.1016/j.drugalcdep.2011.10.012. | |
| Human μ-opioid receptor variant 118 A>G (rs1799971) | Meta-analysis of 14 studies: Cohen’s d = 0.096; p = 0.008), consisting of higher opioid dosing requirements in peri- and post-operative settings. Cohen is very conservative and as such the rs1799971 due to its small effect size, the SNP should be regarded as a part of complex genotypes underlying pain and analgesia. | Meta-analysis of 14 studies The population total was 3446 (N=1476 G carriers and 1970-on G carriers) | Walter C, Doehring A, Oertel BG, Lötsch J. μ-opioid receptor gene variant OPRMI 118 A>G: a summary of its molecular and clinical consequences for pain. Pharmacogenomics. 2013 Nov;14(15):1915-25. doi: 10.2217/pgs.13.187. | |
| OPRMI mRNA-expression in prefrontal cortex | The functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of other haplotypes. | Tested 103 OPRMI SNPs for association with OPRMI mRNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry. Final analysis dataset included N =852 African Americans (307 DSM-IV-defined cases of heroin/other opioid abuse or dependence and 545 controls with no illicit drug abuse or dependence. | Hancock DB, Levy JL, Gaddis NC, Glasheen C, Saccone NL, Page GP, Hulse GK, Wildenauer D, Kelty EA, Schwab SG, Degenhardt L, Martin NG, Montgomery GW, Attia J, Holliday EG, McEvoy M, Scott RJ, Bierut LJ, Nelson EC, Krai AH, Johnson EO. Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRMI. Biol Psychiatry. 2015 Oct 1;78(7):474-84. doi: 10.1016/j.biopsych.2015.01.003. Epub 2015 Jan 29. PubMed PMID: 25744370; PubMed Central PMCID: PMC4519434. | |
| OPRMI gene, All8G (rs1799971, Asn40Asp) | OPRMI A118G SNP Gil8 allele carriers showed significantly higher levels of AD severity as indicated by the MAST | N=121 Alcohol dependent (AD) patients and N= 117 healthy male subjects were included in the | Gurel ŞC, Ayhan Y, Karaaslan Ç, Akel H, Karaca RÖ, BabaoĞlu MÖ, Yaşr Ü, Bozkurt A, Dilbaz N, UluĞ BD, Demir B. μ-Opioid Receptor Gene (OPRMI) Polymorphisms A118G and C17T in Alcohol Dependence: A Turkish Sample. Turk Psikiyatri Derg. 2016 Summer;27(2):0. | |
| OPRMI (rs1799971) polymorphism | Research shows that there are differences in the genotypes and alleles of the OPRMI polymorphism in the case-control study | An association study of a group of Alcohol Dependent Syndrome (ADS) patients (n = 177) and control group consisted of healthy volunteers, with matched gender and age, and with psychiatric disorders excluded (η = 162). | Samochowiec A, Samochowiec J, Pelka-Wysiecka J, Kucharska-Mazur J, Grochans E, Jabłoński M, Bieńkowski P, Murawiec S, Małecka I, Mak M, Kołodziej Ł, Heitzman J, Grzywacz A. The role of OPRMI polymorphism in the etiology of alcoholism. Adv Clin Exp Med. 2019 Feb;28(2):199-202. doi: 10.17219/acem/78592. | |
| A single gene, OPRM1, encodes the MIOR | Results indicate that 118G allele carriers reported significantly more heroin use-related consequences and heroin-quit attempts, and were more likely to have sought treatment for their heroin use than 118AA homozygotes. | Caucasian chronic heroin users (n = 86). | Woodcock EA, Lundahl LH, Burmeister MI, Greenwald MK. Functional mu opioid receptor polymorphism (OPRMIl A(118) G) associated with heroin use outcomes in Caucasian males: A pilot study. Am J Addict. 2015 Jun;24(4):329-35. doi: 10.1111/ajad.12187. Epub 2015 Apr 24. PubMed PMID: 25911999; PubMed Central PMCID: PMC5541380. | |
| A118G rs1799971 polymorphism | When the authors assessed the associations of this polymorphism with the presence or absence of alcohol use disorder through the AUDIT score, we found that, after covariate adjustment, male carriers of the G allele had an increased risk of presenting an alcohol pattern consumption compatible with AUD (OR=2.52; 95% CI: 1.02-6.24;; p = 0.046). The conclusion is that these results suggest that OPRM1 gene polymorphisms are associated with tobacco and alcohol consumption in a Spanish population, and this association could be modulated by genetic and environmental factors. | N=763 unrelated individuals (465 women, 298 men) aged 18-85 years were recruited between October 2011 and April 2012. Participants were requested to answer a 3 5-item questionnaire on tobacco and alcohol consumption, as well as to complete the AUDIT and Fagerstrom tests. | Frances F, Portoles O, Castello A, Costa JA, Verdú F. Association between Opioid Receptor mu 1 (OPRM1) Gene Polymorphisms and Tobacco and Alcohol Consumption in a Spanish Population. Bosn J Basic Med Sci. 15(2):31-6. doi: 10.17305/bjbms.2015.243. PubMed PMID: 26042510; PubMed Central PMCID: PMC4469933. | |
| GABRB3 | GABRB3 promotor Alpha-3 CA-repeat 181 (downstream) CHr15 | Data suggest that GABRB3 might be associated with heroin dependence, and increased expression of GABRB3 might contribute to the pathogenesis of heroin dependence. | A case-control association analysis between N=576 subjects with heroin dependence (549 males, 27 females) and 886 controls (472 males, 414 females) | Chen CH, Huang CC, Liao DL. Association analysis of GABRB3 promoter variants with heroin dependence. PLoS One. 2014 Jul 15;9(7):e102227. doi: 10.1371/journal.pone.0102227. PubMed PMID: 25025424; PubMed Central PMCID: PMC4098998. |
| Chr-15-RS2677918 9(Upstream) Risk CT | For this allele it was found that the BRBR3 significantly associated with both heroin and cocaine risk (P<.003). This study suggests numerous potential susceptibility loci (or markers that tag them) in the glutamatergic and GABAergic pathways for heroin and cocaine addiction, in subjects of African and European ancestry, with partial overlap in susceptibility loci between populations and between addictions to different drugs. | Total population N=1860; N=1142=Heroin subjects; and 439 controls ; Eastern European / middle Eastern = N= 827 Heroin and 232 Controls; African-American (AA) =315 heroin and 207 controls; AA=279 Cocaine Total 1860 = 1142 h; 279 cocaine and 439 controls | Levran O, Peles E, Randesi MI, Correa da Rosa J, Ott J, Rotrosen J, Adelson MI, Kreek MIJ. Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:118-23. doi: 10.1016/j.pnpbp.2015.08.003. Epub 2015 Aug 12. PubMed PMID: 26277529; PubMed Central PMCID: PMC45 64302. | |
| Receptor beta3 subunit (GABRB3) 181 variant | When the DRD2 and the GABRB3 variants are combined, the risk for alcoholism is more robust than when these variants are considered separately. | Determined in a population-based association study of Caucasian non-alcoholic and alcoholic subjects. In severe alcoholics, compared to non-alcoholics | Noble EP, Zhang X, Ritchie T, Lawford BR, Grosser SC, Young RMI, Sparkes RS. D2 dopamine receptor and GABA(A) receptor beta3 subunit genes and alcoholism. Psychiatiy Res. 1998 Nov 16;81(2):133-47. | |
| GABRB3 CHR 15 | All combinations of genes, a count of the number of hypodopaminergic genotypes. Hypodopaminergic functioning predicted drug use in males; however, in females, a deleterious environment was the salient predictor. This preliminary study suggests that it is possible to identify children at risk for problematic drug use prior to the onset of drug dependence. | Variables included in the study were dopaminergic genes (ANXK1 TaqI A, DRD2 C957T, DRD4 7R, COMT Val/Met substitution, and SLC6A3 9R) and a GABAergic gene (GABRB3). Genotyping adolescent Caucasian children of alcoholics (N=57 males, N =54 females; mean age = 14.5 years) | Conner BT, Hellemann GS, Ritchie TL, Noble EP. Genetic, personality, and environmental predictors of drug use in adolescents. J Subst Abuse Treat. 2010 Mar;38(2):178-90. doi: 10.1016/j.jsat.2009.07.004. | |
| MAOA | 30 BP VNTR-3.5R, 4R DN repeat polymorphisms | Significant associations of alcohol dependence with MAOA alleles (RFLP and DNRP) were found among the Han Chinese. It is concluded that MAOA mutations may play a role in susceptibility to alcoholism among Han Chinese | Male alcoholic patients and nonalcoholic comparison subjects among Han Chinese | Hsu YP, Loh EW, Chen WJ, Chen CC, Yu JMI, Cheng AT. Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan. Am J Psychiatry. 1996 Sep;153(9):1209-11. |
| 30 BP VNTR-3.5R, 4R DN repeat polymorphisms | High activity 4-repeat allele frequency Buss Durkee Hostility Inventory (BDHI) mean total scores were significantly higher in heroin addicts than in controls (p<0.001) | N=199 male subjects of Italian descent, a sample comprising 95 healthy subjects and N= 104 heroin-dependent subjects | Gerra G, Garofano L, Bosari S, Pellegrini C, Zaimovic A, Moi G, Bussandri M, Moi A, Brambilla F, Mameli A, Pizzamiglio M, Donnini C. Analysis of monoamine oxidase A (MAO-A) promoter polymorphism in male heroin-dependent subjects: behavioural and personality correlates. J Neural Transm (Vienna). 2004 May;111(5):611-21. | |
| Dinucleotide repeat length polymorphism at the MAOA | A significant correlation between the presence/absence of the disorder and the length of the MAOCA-1 repeat was found in males, but not females, with “long” alleles (repeat length above 115 bp) associated with both increased risk for the disorder and lower age of onset of substance abuse. | An association between the liability to early onset alcoholism/substance abuse and a recently discovered dinucleotide repeat length polymorphism at the MAOA gene (MAOCA-1) was examined using polymerase chain reaction (PCR). | Vanyukov MM, Moss HB, Yu LM, Tarter RE, Deka R. Preliminary evidence for an association of a dinucleotide repeat polymorphism at the MAOA gene with early onset alcoholism/substance abuse. Am J Med Genet. 1995 Apr 24;60(2):122-6. | |
| High activity allele (L: 4 repeats (4R)) of MAOA-LPR | MAOA-LPR may have predictive effects on co-morbid BPD in female heroin-dependent patients; | N=296 female heroin-dependent patients (including 61 patients with Borderline Personality Disorder(BPD )and 235 without BPD) and N= 101 normal females | Yang M, Mamy J, Wang Q, Liao YH, Seewoobudul V, Xiao SY, Hao W. The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and borderline personality disorder in female heroin-dependent Chinese subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Apr 3;50:74-82. doi: 10.1016/j.pnpbp.2013.12.005. | |
| Transcript factor TFAP2b regulates MAOA | Results showed that the high-functioning allele was significantly more common among the female alcoholics, compared to the nonalcoholic controls. This suggest that high allele would up-regulate MAO-A Long 3.5 to 4R | Compared a sample of female alcoholics (n=107), sentenced to institutional care for their severe addiction, contrasted against a control sample of adolescent females (n=875) | Nordquist N, Gokturk C, Comasco E, Nilsson KW, Oreland L, Hallman J. Transcription factor AP2 beta involved in severe female alcoholism. Brain Res. 2009 Dec 11;1305 Suppl:S20-6. doi: 10.1016/j.brainres.2009.09.054 | |
| SLC6A4(5HTTLPR) | 43BP-INDEL/VNTR CHR17-rs25531 LG, S | By univariate ANOVA, a statistically significant difference was found in the onset of AD: the mean age of onset resulted to be of 25.4 years in males in respect to 28.1 in females. In particular in males, the early AD onset was different, in a statistically significant manner, depending on the presence of at least one S. | Genotyping of the 5-HTTLPR (L/S) and rs25531 (A/G) polymorphisms of the SLC6A4 gene was performed on N= 403 alcoholics outpatients and N=427 blood donors. | Pascale E, Ferraguti G, Codazzo C, Passarelli F, Mancinelli R, Bonvicini C, Bruno SM, Lucarelli M, Ceccanti M. Alcohol dependence and serotonin transporter functional polymorphisms 5-HTTLPR and rs25531 in an Italian population. Alcohol Alcohol. 2015 May;50(3):259-65. doi: 10.1093/alcalc/agv014. |
| promoter region (5-HTTLPR) (rs25531) | The genotype frequencies of the 5-HTTLPR S+ (S/S, S/LG, LG/LG) polymorphisms were significantly higher in opiate-dependent patients ( p = 0.01). There was a significant interaction between the TPH1 A218C A/C and 5-HTTLPR S+ gene polymorphisms in opiate-dependent (OR 2.72, p = 0.01), | Opiate-dependent patients (n = 309), and healthy controls (n = 301) were recruited from the Han Chinese population in Taiwan. | Wang TY, Lee SY, Chung YL, Chen SL, Li CL, Chang YH, Wang LJ, Chen PS, Chen SH, Chu CH, Huang SY, Tzeng NS, Hsieh TH, Lee IH, Chen KC, Yang YK, Hong JS, Lu RB. TPH1 and 5-HTTLPR Genes Specifically Interact in Opiate Dependence but Not in Alcohol Dependence. Eur Addict Res. 2016;22(4):201-9. doi: 10.1159/000444676. | |
| rs25531 polymorphisms of SLC6A4 gene | The biallelic analysis revealed that the frequency of 5-HTTLPR (LL/LS/SS) genotypes was statistically significant different between drug-dependent individuals and controls ( p = 0.04) | Jordanian drug male addicts of Arab descent (n = 192) meeting the Diagnostic and Statistical Manual of Mental Disorders - Fourth edition criteria for drug dependence and 230 healthy male controls from an ethnically homogenous Jordanian Arab population were examined. | Al-Eitan LN, Jaradat SA, Qin W, Wildenauer DM, Wildenauer DD, Hulse GK, Tay GK. Characterization of serotonin transporter gene (SLC6A4) polymorphisms and its association with drug dependence in a Jordanian Arab population. Toxicol Ind Health. 2014 Aug;30(7):598-610. doi: 10.1177/0748233712462446. |