Association of Variants in MANEA With Cocaine-Related Behaviors

Context: Cocaine dependence (CD) and related behaviors are highly heritable, but no genetic association has been consistently demonstrated. A recent genome-wide study of drug dependence identified an association between cocaine-induced paranoia (CIP) and a single-nucleotide polymorphism (SNP) in the alpha-endomannosidase (MANEA) locus in a family-based sample of European Americans and African Americans. Objective: To conduct a comprehensive genetic association study of the MANEA locus with CD and CIP. Design: Genome-wide association study. Setting: Four university hospitals. Participants: A total of 3992 individuals from 2 family-based and 2 case-control samples. Intervention: Participants were classified as having CD or CIP or as a control using the Semi- Structured Assessment for Drug Dependence and Alcoholism. They were genotyped for 11 SNPs spanning MANEA and its surrounding region. Main Outcome Measure: Association of CD and CIP with individual SNPs and haplotypes. Results: Cocaine-induced paranoia was associated with 6 SNPs in the European American families and 9 SNPs in the African American families. The strongest evidence in the total sample of families was observed in 3 markers located in the promoter and 3' untranslated regions (P < .001). The association of MANEA SNPs with CD in both family samples was much weaker. In the African American case-control sample, multiple markers were significantly associated with CIP and CD; CIP and CD were also significantly associated with a 2-SNP haplotype in the European American case-control sample. The A allele of the 3' untranslated region SNP rs9387522 was associated with increased risk of CIP in all 4 data sets. Conclusions: Our findings suggest that CD and associated behaviors may involve biological pathways not typically thought to be associated with brain metabolism.