Association of variants in MANEA with cocaine-related behaviors.
BACKGROUND
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.


METHODS
Genome-wide association study.


METHODS
Four university hospitals.


METHODS
A total of 3992 individuals from 2 family-based and 2 case-control samples.


METHODS
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.


METHODS
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.
Farrer
Lindsay A
LA
Genetics Program, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. farrer@bu.edu
Kranzler
Henry R
HR
Yu
Yi
Y
Weiss
Roger D
RD
Brady
Kathleen T
KT
Anton
Raymond
R
Cubells
Joseph F
JF
Gelernter
Joel
J
D000328:Adult; D000483:Alleles; D002874:Chromosome Mapping; D019970:Cocaine-Related Disorders / Q000175:diagnosis / Q000208:ethnology* / Q000235:genetics*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008361:Mannosidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D044469:Racial Groups / Q000235:genetics
D008361:Mannosidases