Association Between Polymorphisms in Catechol-O-methyltransferase (COMT) and Cocaine-Induced Paranoia in European-American and African-American Populations

• Type of Material: Article
• Authors: Rungnapa Ittiwut, VA Connecticut Healthcare System; Jennifer B. Listman, Yale University; Chupong Ittiwut, VA Connecticut Healthcare System; Joseph Cubells, Emory University; Roger D. Weiss, McLean Hospital; Kathleen Brady, Medical University of South Carolina; David Oslin, University of Pennsylvania; Lindsay A. Farrer, Boston University; Henry R. Kranzler, University of Connecticut; Joel Gelernter, Yale University
• Language: English
• Date: 2011-09-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc..
• Final Published Version (URL): http://dx.doi.org/10.1002/ajmg.b.31205
• Title of Journal or Parent Work: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
• ISSN: 1552-4841
• Volume: 156B
• Issue: 6
• Start Page: 651
• End Page: 660
• Grant/Funding Information: Supported by the NIH (NIDA) grants R01 DA12690, R01 DA12849, R01 AA0175350, R01 AA11330, D43 TW06166, and K24 DA022288; GCRC M01 RR06192; and the US Department of Veterans Affairs (the VA Connecticut-Massachusetts Mental Illness Research, Education and Clinical Center (MIRECC)), and families who participated in this study.
• Keywords: cocaine-induced paranoia; family-based analysis; haplotype; Life Sciences & Biomedicine; HUMAN BRAIN; Science & Technology; 22Q11.2 DELETION SYNDROME; SNP; DBH LOCUS; MESSENGER-RNA; HAPLOTYPE; COMT; GENOMEWIDE LINKAGE SCAN; GENETIC-VARIATION; FUNCTIONAL POLYMORPHISM; BETA-HYDROXYLASE ACTIVITY; positive selection; Genetics & Heredity; Psychiatry; DEPENDENCE
• Research Categories: Psychology, Psychobiology; Biology, Genetics; Sociology, Ethnic and Racial Studies

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.