Pro-Opiomelanocortin Gene Variation Related to Alcohol or Drug Dependence: Evidence and Replications Across Family- and Population-based Studies

Background: Opioidergic neurotransmission is critical in many, possibly all, forms of substance dependence. Several opioid-system genes have been shown to be associated with substance dependence disorders. The pro-opiomelanocortin gene (POMC) encodes several peptides important for endogenous opioidergic neurotransmission. We tested whether POMC genetic variation affects risk for substance dependence. Methods: Five single nucleotide polymorphisms spanning POMC were examined in independent family and case-control samples. Family-based studies included 854 subjects from 319 African American (AA) families and 761 subjects from 313 European American (EA) families. Each family had a pair of siblings affected with cocaine and/or opioid dependence. Case-control studies included 791 cases (455 AAs and 336 EAs) affected with alcohol, cocaine, and/or opioid dependence and 682 control subjects (199 AAs and 483 EAs). Results: Family-based analyses revealed an association of rs6719226 with opioid dependence in AA families and rs6713532 with cocaine dependence in EA families (p = .010-044). Case-control analyses demonstrated an association of rs6713532 with alcohol or cocaine dependence in EAs (Pallele-wise = .003-008). Moreover, the minor allele of rs1866146 was found to be a risk factor for cocaine or opioid dependence in AAs (p(allele-wise) = .010-.017) and for alcohol, cocaine, or opioid dependence in EAs (p(allele-wise) = .001-.003). Logistic regression analyses in which sex and age were considered and population stratification analyses confirmed these findings. Additionally, specific haplotypes increased risk for cocaine dependence (p = .023) in AAs and opioid dependence (p = .012) in EAs. Conclusions: Given these replicated results, we conclude that variation in POMC confers vulnerability to multiple forms of substance dependence.