The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

• Published in: Molecular psychiatry Vol. 13; no. 5; pp. 531 - 543
• Main Authors: Zhang, H, Kranzler, H R, Yang, B-Z, Luo, X, Gelernter, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2008; Nature Publishing Group
• Subjects: Addictive behaviors; Adolescent; Adult; Adult and adolescent clinical studies; Aged; Alcohol; Alcoholism; Alcoholism - genetics; Alleles; Analgesics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Case-Control Studies; Cocaine; Cocaine-Related Disorders - genetics; Dopamine; Drug abuse; Drug addiction; Drug dependence; Europe - ethnology; Exons - genetics; Female; Gene frequency; Genetic aspects; Genetic Predisposition to Disease; Haplotypes; Haplotypes - genetics; Health aspects; Heroin Dependence - genetics; Humans; Linkage Disequilibrium; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Morphine; Narcotics; Neurosciences; Opioids; original-article; Peptides; Pharmacotherapy; Polymorphism, Single Nucleotide; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors; Receptors, Opioid, delta - genetics; Receptors, Opioid, delta - physiology; Receptors, Opioid, kappa - genetics; Receptors, Opioid, kappa - physiology; Regression analysis; Risk; Risk factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Substance-Related Disorders - genetics; United States - epidemiology; United States; Europe; United States > US; opioid receptor genes; logistic regression; single nucleotide polymorphism; alcohol or drug dependence; haplotype trend regression; association study; Human; Drug addiction; Illicit drug; Alcoholism; Opioid receptor; Genetic determinism; Alcoholic beverage; Logistic regression; Addiction; Gene; Risk factor; Genetics; Single nucleotide polymorphism; Haplotype
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4002035

Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations ( P <0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype G CAA C T, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD ( χ 2 =14.82, degrees of freedom (d.f.)=1, P <0.001), CD ( χ 2 =9.19, d.f.=1, P =0.002) and OD ( χ 2 =20.68, d.f.=1, P <0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD ( P =0.03, β =1.86, odds ratio (OR)=6.43) and especially on OD ( P <0.001, β =3.92, OR=50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD ( χ 2 =8.12, d.f.=1, P =0.004). Logistic regression analyses also revealed its risk effect on AD ( P =0.009, β =1.06, OR=2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.