Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations

Authors

  • Rungnapa Ittiwut,

    1. Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut
    2. VA Connecticut Healthcare System, West Haven, Connecticut
    3. Department of Medical Services, Institute of Pathology, Ministry of Public Health, Bangkok, Thailand
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  • Jennifer B. Listman,

    1. Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut
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  • Chupong Ittiwut,

    1. Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut
    2. VA Connecticut Healthcare System, West Haven, Connecticut
    3. Chulalongkorn GenePRO Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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  • Joseph F. Cubells,

    1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
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  • Roger D. Weiss,

    1. McLean Hospital, Belmont, MA
    2. Harvard Medical School, Boston, Massachusetts
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  • Kathleen Brady,

    1. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
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  • David Oslin,

    1. Philadelphia VA Medical Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Lindsay A. Farrer,

    1. Department of Medicine (Genetics), Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
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  • Henry R. Kranzler,

    1. Department of Psychiatry and Genetics and Developmental Biology, University of Connecticut School of Medicine, Farmington, Connecticut
    Current affiliation:
    1. Philadelphia VA Medical Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
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  • Joel Gelernter

    Corresponding author
    1. Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut
    2. VA Connecticut Healthcare System, West Haven, Connecticut
    3. Department of Genetics, New Haven, Connecticut
    4. Department of Neurobiology, New Haven, Connecticut
    • Yale University School of Medicine, VAMC 116A2, 950 Campbell Avenue, West Haven, CT 06516.
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  • Conflict of Interest: Dr. Kranzler has been a paid consultant for Alkermes, GlaxoSmithKline, and Gilead. He has received research support from Merck. He also reports associations with Eli Lilly, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson, as these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and Dr. Kranzler receives support from ACTIVE.

  • How to Cite this Article: Ittiwut R, Listman JB, Ittiwut C, Cubells JF, Weiss RD, Brady K, Oslin D, Farrer LA, Kranzler HR, Gelernter J. 2011. Association Between Polymorphisms in Catechol-O-methyltransferase (COMT) and Cocaine-Induced Paranoia in European-American and African-American Populations. Am J Med Genet Part B 156:651–660.

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. © 2011 Wiley-Liss, Inc.

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