title: Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations.
abstract: Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine.
authors.affiliation: Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut 06516, USA.
authors.forename: Rungnapa
authors.initials: R
authors.lastname: Ittiwut
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Listman
authors.forename: Chupong
authors.initials: C
authors.lastname: Ittiwut
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cubells
authors.forename: Roger D
authors.initials: RD
authors.lastname: Weiss
authors.forename: Kathleen
authors.initials: K
authors.lastname: Brady
authors.forename: David
authors.initials: D
authors.lastname: Oslin
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010259:Paranoid Disorders / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*
chemical_list: D002394:Catechol O-Methyltransferase; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine