MU-OPIOID RECEPTOR GENE VARIANTS - LACK OF ASSOCIATION WITH ALCOHOL DEPENDENCE

The mu opioid receptor is implicated in the reward, tolerance and with drawal effects of alcohol and other drugs of abuse.(1,2) This hypothes is is supported by the effects of alcohol on beta-endorphin release,(3 ) of mu opioid receptor agonists and antagonists on alcohol consumptio n,(4,5) and by the activation of the dopaminergic reward system by bot h alcohol and opiates.(6) In addition, the murine mu opioid receptor l ocus, Oprm, is implicated as the major quantitative trait locus (QTL) affecting the different levels of morphine consumption between two inb red mouse strains that also exhibit differences in alcohol and cocaine consumption.(7,8) Detection of genetic variation affecting OPRM1 expr ession or mu opioid receptor function would be an important step towar ds understanding the origins of inter-individual variation in response to mu opioid receptor ligands and in diseases of substance dependence .(9-12) We directly sequenced the human mu opioid receptor locus, OPRM 1,(13-15) to detect natural variation that might affect function and/o r be associated with psychiatric phenotypes related to opioid function . Four DNA sequence variants were found: three non-synonymous substitu tions (Ala6Val [rare], Asn40Asp, [0.10-0.16], Ser147Cys [rare]) and on e intronic variant (IVS2+691G/C [0.55-0.63]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population sa mples (US Caucasian [USC, n = 100], Finnish Caucasian [FC, n = 324] an d Southwestern American Indian [SAI, n = 367]), were used to perform a ssociation and sib-pair linkage analyses with alcohol and drug depende nce diagnoses. No significant association of OPRM1 genetic variation t o phenotype was observed. This analysis has 80% power to detect a smal l to moderate effect of OPRM1 variation on alcohol dependence and 100% power to detect effects of the magnitude of the ALDH22 variant. Whil e these data do not support a role of the mu opioid receptor in suscep tibility to alcohol dependence, the potential relationship between OPR M1 genetic variation and response to endogenous opioids and exogenous opiates can now be investigated.