Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations.
- Authors
- Ittiwut, Rungnapa; Listman, Jennifer B; Ittiwut, Chupong; Cubells, Joseph F; Weiss, Roger D; Brady, Kathleen; Oslin, David; Farrer, Lindsay A; Kranzler, Henry R; Gelernter, Joel
- Year
- 2011
- Journal
- American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
- PMID
- 21656904
- DOI
- 10.1002/ajmg.b.31205
- PMCID
- PMC3864552
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.
Pairwise LD of COMT gene in African-American (AA) and European-American (EA) families. AAs showed three short blocks and EAs showed two short blocks. Numbers 1 to 17 represent SNPs correlating with rs number in Table II across COMT gene. All COMT exons (the dark box represents coding region and the clear box represent the noncoding region; 3′ and 5′ UTR) shown in the center of picture include the position of the 17 SNPs genotyped in this study. From haploview, the bright red box represents D′ = 1 and LOD = 2, shades of pink/red represent D′ < 1 and LOD = 2, blue represents D′ = 1 and LOD < 2, and white represents D′ < 1 and LOD < 2.
A core region of SNPs 2–5 within the 15-SNP haplotype includes rs933271, rs5993883, rs739368, and rs740603. The two populations display opposite patterns of homozygosity and frequency of haplotypes. The haplotype in which alleles are derived for rs933271, rs5993883, and rs740603 (T–T–C–A) is the most common in EAs and also has higher homozygosity than the three ancestral allele haplotype (C–G–C–G). The three derived allele haplotype is less common than the three ancestral allele haplotype in AAs and also has lower homozygosity. Graphics produced using the web-based Extended Haplotype Homozygosity Calculator and Plotter (http://ihg.gsf.de/cgi-bin/mueller/webehh.pl).
Relative extended haplotype homozygosity (REHH) calculated with Sweep software (http://www.broad.mit.edu/mpg/sweep/index.html) for EA and AA samples. REHH measures the comparative decay of homozygosity for one haplotype among haplotypes of a given core. The 15-SNP haplotypes compared have, for a core region of SNPs 2–5, either derived or ancestral alleles for the core SNPs.
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| New Evidence of The Reliability of The <i>Scale for The Assessment of Positive Symptoms of Cocaine Induced Psychosis</i> (SAPS-CIP-R) in a Sample of Cocaine Users Treated at a Therapeutic Community. | González-Saiz F et al. | — | 2026 | → |
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| A prospective, longitudinal study to evaluate the clinical utility of a predictive algorithm that detects risk of opioid use disorder. | Brenton A et al. | — | 2018 | → |
| Association of genetic variation in <i>COMT</i> gene with pain related to sickle cell disease in patients from the walk-PHaSST study. | Zhang Y et al. | — | 2018 | → |
| Dopamine gene variants in opioid addiction: comparison of dependent patients, nondependent users and healthy controls. | Randesi M et al. | — | 2018 | → |
| Environmental, genetic and epigenetic contributions to cocaine addiction. | Pierce RC et al. | — | 2018 | → |
| Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity. | Wachman EM et al. | — | 2017 | → |
| Catechol-O-methyltransferase Gene Polymorphism (Val158Met) and Development of Pre-eclampsia. | Taravati A et al. | — | 2017 | → |
| The genetic epidemiology of substance use disorder: A review. | Prom-Wormley EC et al. | — | 2017 | → |
| Validation Study of a Predictive Algorithm to Evaluate Opioid Use Disorder in a Primary Care Setting. | Sharma M et al. | — | 2017 | → |
| Interaction between COMT rs5993883 and second generation antipsychotics is linked to decreases in verbal cognition and cognitive control in bipolar disorder. | Flowers SA et al. | — | 2016 | → |
| A review of pharmacogenetic studies of substance-related disorders. | Jones JD et al. | — | 2015 | → |
| COMT Val158Met polymorphism is associated with blood pressure and lipid levels in general families of Bama longevous area in China. | Ge L et al. | — | 2015 | → |
| Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans. | Levran O et al. | — | 2015 | → |
| The nutrigenetic influence of the interaction between dietary vitamin E and TXN and COMT gene polymorphisms on waist circumference: a case control study. | Mansego ML et al. | — | 2015 | → |
| Variations in opioid receptor genes in neonatal abstinence syndrome. | Wachman EM et al. | — | 2015 | → |
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