Abstract
Polymorphisms in the μ-, δ- and κ-opioid receptor genes (OPRM1, OPRD1 and OPRK1) have been reported to be associated with substance (alcohol or drug) dependence. The influence of an individual gene on a disease trait should be more evident when analyzed in the context of gene-gene interactions. Thus, we assessed the joint effect of variants in these three opioid receptor genes on alcohol, cocaine, or opioid dependence. Genotype data for 13 OPRM1 Single Nucleotide Polymorphisms (SNPs), 11 OPRD1 SNPs and seven OPRK1 SNPs were obtained from 382 European Americans (EAs) affected with substance dependence [among them, 318 with Alcohol Dependence (AD), 171 with Cocaine Dependence (CD), and 91 with Opioid Dependence (OD)] and 338 EA control subjects. We assessed the joint effect of OPRM1, OPRD1 and OPRK1 variants on AD, CD, or OD using a pattern discovery-based association test. Specific marker patterns (consisting of alleles of OPRM1, OPRD1 and OPRK1) that were significantly more frequent in AD, CD, or OD cases than in controls were identified. 12 significant patterns in the AD dataset, four significant patterns in the CD dataset, and 18 significant patterns in the OD dataset were identified. Moreover, the significance of most marker patterns was due primarily to OPRM1 variants and, to a lesser degree, OPRD1 variants. Our findings suggest that variation in the above three opioid receptor genes can jointly influence the vulnerability of individuals to alcohol or drug dependence. Evidence provided by this study also supports previous biological findings that the interaction of the three opioid receptors can modulate the action of opioid and non-opioid drugs and alcohol.
Highlights
Substance dependence, such as alcohol, cocaine, or opioid dependence, is a set of genetically complex disorders due to the effect of a number of different individual disease genes or a combination of different disease genes
Our findings suggest that variation in the above three opioid receptor genes can jointly influence the vulnerability of individuals to alcohol or drug dependence
We examined the association of 13 OPRM1 SNPs, 11 OPRD1, and seven OPRK1 SNPs with alcohol or drug dependence
Summary
Substance dependence, such as alcohol, cocaine, or opioid dependence, is a set of genetically complex disorders due to the effect of a number of different individual disease genes (heterogeneity) or a combination of different disease genes (polygeneity). There is evidence that the three opioid receptor genes (OPRM1, at 6q24-q25, which encodes the μ-opioid receptor; OPRD1, at 1p36.1-p34.3, which encodes the δ-opioid receptor; and OPRK1, at 8q11.2, which encodes the κ-opioid receptor) could be such common genetic factors [3,4,5,6]. There is mounting evidence that the three receptors directly mediate reward, tolerance, and dependence associated with opioids [7,8]. They are indirectly involved in the reinforcing properties of non-opioid drugs (such as cocaine and alcohol) due to the intimate relationship between the opioid system and the mesolimbic dopamine system. Polymorphisms in the μ-, δ- and κ-opioid receptor genes (OPRM1, OPRD1 and OPRK1) have been reported to be associated with substance (alcohol or drug) dependence. We assessed the joint effect of variants in these three opioid receptor genes on alcohol, cocaine, or opioid dependence
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