前言:
多巴胺(dopamine)系統在雙極症及酒癮的機制上均很重要。因此研究與代謝多巴胺有關的酶的基因或多巴胺受體的基因，包含甲型單胺氧化酶 (monoamine oxidase A ，簡稱MAOA) 與多巴胺第二型受體 (dopamine D2 receptor，簡稱DRD2)基因，對於了解酒癮合併雙極症具關鍵性。因此我們進行本實驗，預計研究MAOA-uNTR 和DRD2 Taq IA此二基因的多型性與酒癮合併雙極症的相關性。
方法 :
本研究為橫斷面研究，採個案對照研究設計。共收集了101個漢族男性酒癮合併雙極症的病人以及328個健康對照組，並進行MAOA-uNTR 和DRD2 Taq IA基因型的檢定。
結果 :
MAOA-uNTR 和DRD2 Taq IA基因型在酒癮合併雙極症的病人以及健康對照組間無顯著差異。邏輯迴歸分析發現MAOA-uVNTR 3-repeat為酒癮合併雙極症的保護因子 (odds ratio=0.43, p=0.04)，但MAOA-uVNTR 3-repeat與DRD2 Taq-IA1/A2交互作用後，即為酒癮合併雙極症的危險因子 (odds ratio=3.54, p=0.02)。
結論 :
MAOA-uNTR 和DRD2 Taq IA基因的多型性可能與酒癮合併雙極症有關。

Background
Several studies have hypothesized that genes involved in the dopamine system, including dopamine type-2 receptor (DRD2)-related TaqIA polymorphism and monoamine oxidase-A upstream variable number tandem repeat (uVNTR), may be associated with alcoholism. But their results were contradictory because of alcoholism’s heterogeneity. Therefore, we examined whether the DRD2TaqIA and MAOA-uVNTR gene polymorphisms are susceptibility factors for alcoholism comorbid with bipolar disorder (ALC+BP) in male Han Chinese in Taiwan.
Methods
We recruited 101 male Han Chinese men with comorbid alcoholism and bipolar disorder, and 328 healthy male controls from the community. Genotyping was done using PCR-RFLP.
Results
There were no significant differences in the genotypic frequencies of the DRD2TaqIA or the MAOA-uVNTR polymorphisms between the 2 groups. The MAOA-uVNTR 3-repeat had a significant protective effect on the ALC+BP (odds ratio = 0.43, p = 0.04) but not on the healthy controls. However, the interaction between the MAOA-uVNTR 3-repeat and DRD2 A1/A2 was a risk factor in the ALC+BP (odds ratio = 3.54, p = 0.02).
Conclusions
We indicated the impact of the association between MAOA-uVNTR 3-repeat and DRD2 A1/A2 with ALC+BP.

Amadeo, S., Abbar, M., Fourcade, M. L., Waksman, G., Leroux, M. G., Madec, A., . . . et al. (1993). D2 dopamine receptor gene and alcoholism. J Psychiatr Res, 27(2), 173-179.
Bauer, M. S., Simon, G. E., Ludman, E., & Unutzer, J. (2005). 'Bipolarity' in bipolar disorder: distribution of manic and depressive symptoms in a treated population. Br J Psychiatry, 187, 87-88.
Berman, S. M., & Noble, E. P. (1997). The D2 dopamine receptor (DRD2) gene and family stress; interactive effects on cognitive functions in children. Behav Genet, 27(1), 33-43.
Blum, K., Braverman, E. R., Holder, J. M., Lubar, J. F., Monastra, V. J., Miller, D., . . . Comings, D. E. (2000). Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs, 32 Suppl, i-iv, 1-112.
Blum, K., Noble, E. P., Sheridan, P. J., Montgomery, A., Ritchie, T., Jagadeeswaran, P., . . . Cohn, J. B. (1990). Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA, 263(15), 2055-2060.
Buckland, P. R. (2001). Genetic association studies of alcoholism--problems with the candidate gene approach. Alcohol Alcohol, 36(2), 99-103.
Cloninger, C. R., Bohman, M., & Sigvardsson, S. (1981). Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. Arch Gen Psychiatry, 38(8), 861-868.
Comings, D. E. (1996). Genetic factors in drug abuse and dependence. NIDA Res Monogr, 159, 16-38; discussion 39-48.
Comings, D. E. (1998). Polygenic inheritance and micro/minisatellites. Mol Psychiatry, 3(1), 21-31.
Comings, D. E. (1999). Molecular heterosis as the explanation for the controversy about the effect of the DRD2 gene on dopamine D2 receptor density. Mol Psychiatry, 4(3), 213-215.
Comings, D. E., Muhleman, D., Ahn, C., Gysin, R., & Flanagan, S. D. (1994). The dopamine D2 receptor gene: a genetic risk factor in substance abuse. Drug Alcohol Depend, 34(3), 175-180.
Contini, V., Marques, F. Z., Garcia, C. E., Hutz, M. H., & Bau, C. H. (2006). MAOA-uVNTR polymorphism in a Brazilian sample: further support for the association with impulsive behaviors and alcohol dependence. Am J Med Genet B Neuropsychiatr Genet, 141B(3), 305-308.
Deckert, J., Catalano, M., Syagailo, Y. V., Bosi, M., Okladnova, O., Di Bella, D., . . . Lesch, K. P. (1999). Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet, 8(4), 621-624.
Dick, D. M., & Foroud, T. (2003). Candidate genes for alcohol dependence: a review of genetic evidence from human studies. Alcohol Clin Exp Res, 27(5), 868-879.
Eitle, D. (2005). The moderating effects of peer substance use on the family structure-adolescent substance use association: quantity versus quality of parenting. Addict Behav, 30(5), 963-980.
Endicott, J., & Spitzer, R. L. (1978). A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry, 35(7), 837-844.
Freeman, M. P., Freeman, S. A., & McElroy, S. L. (2002). The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J Affect Disord, 68(1), 1-23.
Goldman, D. (1995). Candidate genes in alcoholism. Clin Neurosci, 3(3), 174-181.
Goldstein, J. L., & Brown, M. S. (1997). The clinical investigator: bewitched, bothered, and bewildered--but still beloved. J Clin Invest, 99(12), 2803-2812.
Grandy, D. K., Zhang, Y., & Civelli, O. (1993). PCR detection of the TaqA RFLP at the DRD2 locus. Hum Mol Genet, 2(12), 2197.
Gutierrez, B., Arias, B., Gasto, C., Catalan, R., Papiol, S., Pintor, L., & Fananas, L. (2004). Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders. Psychiatr Genet, 14(4), 203-208.
Hietala, J., West, C., Syvalahti, E., Nagren, K., Lehikoinen, P., Sonninen, P., & Ruotsalainen, U. (1994). Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology (Berl), 116(3), 285-290.
Huang, S. Y., Lin, M. T., Shy, M. J., Lin, W. W., Lin, F. Y., & Lu, R. B. (2008). Neither single-marker nor haplotype analyses support an association between monoamine oxidase A gene and bipolar disorder. Eur Arch Psychiatry Clin Neurosci, 258(6), 350-356.
Huang, S. Y., Lin, W. W., Ko, H. C., Lee, J. F., Wang, T. J., Chou, Y. H., . . . Lu, R. B. (2004). Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcohol Clin Exp Res, 28(3), 374-384.
Huang, S. Y., Lin, W. W., Wan, F. J., Chang, A. J., Ko, H. C., Wang, T. J., . . . Lu, R. B. (2007). Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence. J Psychiatry Neurosci, 32(3), 185-192.
Huang, Y. Y., Cate, S. P., Battistuzzi, C., Oquendo, M. A., Brent, D., & Mann, J. J. (2004). An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences. Neuropsychopharmacology, 29(8), 1498-1505.
Hwu, H. G., Yeh, E. K., Yeh, Y. L., & Chang, L. Y. (1988). Alcoholism by Chinese diagnostic interview schedule: a prevalence and validity study. Acta Psychiatr Scand, 77(1), 7-13.
Hwu, H. G., Yeh, Y. L., Wang, J. D., & Yeh, E. K. (1990). Alcoholism among Taiwan aborigines defined by the Chinese Diagnostic Interview Schedule: a comparison with alcoholism among Chinese. Acta Psychiatr Scand, 82(5), 374-380.
Jin, Y., Chen, D., Hu, Y., Guo, S., Sun, H., Lu, A., . . . Li, L. (2006). Association between monoamine oxidase gene polymorphisms and smoking behaviour in Chinese males. Int J Neuropsychopharmacol, 9(5), 557-564.
Jonsson, E., Sedvall, G., Brene, S., Gustavsson, J. P., Geijer, T., Terenius, L., . . . Wiesel, F. A. (1996). Dopamine-related genes and their relationships to monoamine metabolites in CSF. Biol Psychiatry, 40(10), 1032-1043.
Kawada, Y., Hattori, M., Dai, X. Y., & Nanko, S. (1995). Possible association between monoamine oxidase A gene and bipolar affective disorder. Am J Hum Genet, 56(1), 335-336.
Kessler, R. C., Borges, G., & Walters, E. E. (1999). Prevalence of and risk factors for lifetime suicide attempts in the National Comorbidity Survey. Arch Gen Psychiatry, 56(7), 617-626.
Kessler, R. C., Rubinow, D. R., Holmes, C., Abelson, J. M., & Zhao, S. (1997). The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychol Med, 27(5), 1079-1089.
Kochersperger, L. M., Parker, E. L., Siciliano, M., Darlington, G. J., & Denney, R. M. (1986). Assignment of genes for human monoamine oxidases A and B to the X chromosome. J Neurosci Res, 16(4), 601-616.
Koller, G., Bondy, B., Preuss, U. W., Bottlender, M., & Soyka, M. (2003). No association between a polymorphism in the promoter region of the MAOA gene with antisocial personality traits in alcoholics. Alcohol Alcohol, 38(1), 31-34.
Lan, N. C., Heinzmann, C., Gal, A., Klisak, I., Orth, U., Lai, E., . . . Shih, J. C. (1989). Human monoamine oxidase A and B genes map to Xp 11.23 and are deleted in a patient with Norrie disease. Genomics, 4(4), 552-559.
Lee, J. F., Lu, R. B., Ko, H. C., Chang, F. M., Yin, S. J., Pakstis, A. J., & Kidd, K. K. (1999). No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Alcohol Clin Exp Res, 23(4), 592-599.
Lee, S. Y., Hahn, C. Y., Lee, J. F., Chen, S. L., Chen, S. H., Yeh, T. L., . . . Lu, R. B. (2009). MAOA-uVNTR polymorphism may modify the protective effect of ALDH2 gene against alcohol dependence in antisocial personality disorder. Alcohol Clin Exp Res, 33(6), 985-990.
Lee, S. Y., Hahn, C. Y., Lee, J. F., Huang, S. Y., Chen, S. L., Kuo, P. H., . . . Lu, R. B. (2010). MAOA interacts with the ALDH2 gene in anxiety-depression alcohol dependence. Alcohol Clin Exp Res, 34(7), 1212-1218.
Lee, S. Y., Lin, W. W., Huang, S. Y., Kuo, P. H., Wang, C. L., Wu, P. L., . . . Lu, R. B. (2009). The relationship between serotonin receptor 1B polymorphisms A-161T and alcohol dependence. Alcohol Clin Exp Res, 33(9), 1589-1595.
Leszczynska-Rodziewicz, A., Hauser, J., Dmitrzak-Weglarz, M., Skibinka, M., Czerski, P., Zakrzewska, A., . . . Rybakowski, J. K. (2005). Lack of association between polymorphisms of dopamine receptors, type D2, and bipolar affective illness in a Polish population. Med Sci Monit, 11(6), CR289-295.
Li, T., Liu, X., Sham, P. C., Aitchison, K. J., Cai, G., Arranz, M. J., . . . Collier, D. A. (1999). Association analysis between dopamine receptor genes and bipolar affective disorder. Psychiatry Res, 86(3), 193-201.
Lim, L. C., Powell, J. F., Murray, R., & Gill, M. (1994). Monoamine oxidase A gene and bipolar affective disorder. Am J Hum Genet, 54(6), 1122-1124.
Lu, R. B., Ko, H. C., Lee, J. F., Lin, W. W., Huang, S. Y., Wang, T. J., . . . Chou, Y. H. (2005). No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan. Alcohol Clin Exp Res, 29(12), 2101-2107.
Lu, R. B., Lee, J. F., Huang, S. Y., Lee, S. Y., Chang, Y. H., Kuo, P. H., . . . Ko, H. C. (2010). Interaction between ALDH2*1*1 and DRD2/ANKK1 TaqI A1A1 genes may be associated with antisocial personality disorder not co-morbid with alcoholism. Addict Biol.
Lu, R. B., Lee, J. F., Ko, H. C., Lin, W. W., Chen, K., & Shih, J. C. (2002). No association of the MAOA gene with alcoholism among Han Chinese males in Taiwan. Prog Neuropsychopharmacol Biol Psychiatry, 26(3), 457-461.
Lu, R. B., Lin, W. W., Lee, J. F., Ko, H. C., & Shih, J. C. (2003). Neither antisocial personality disorder nor antisocial alcoholism is associated with the MAO-A gene in Han Chinese males. Alcohol Clin Exp Res, 27(6), 889-893.
Madrid, G. A., MacMurray, J., Lee, J. W., Anderson, B. A., & Comings, D. E. (2001). Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism. Alcohol, 23(2), 117-122.
Massat, I., Souery, D., Del-Favero, J., Van Gestel, S., Serretti, A., Macciardi, F., . . . Mendlewicz, J. (2002). Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders. Am J Med Genet, 114(2), 177-185.
Merikangas, K. R., Akiskal, H. S., Angst, J., Greenberg, P. E., Hirschfeld, R. M., Petukhova, M., & Kessler, R. C. (2007). Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry, 64(5), 543-552.
Muller, D. J., Serretti, A., Sicard, T., Tharmalingam, S., King, N., Artioli, P., . . . Kennedy, J. L. (2007). Further evidence of MAO-A gene variants associated with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet, 144B(1), 37-40.
Munafo, M. R., Matheson, I. J., & Flint, J. (2007). Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case-control studies and evidence of publication bias. Mol Psychiatry, 12(5), 454-461.
Noble, E. P. (2003). D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet B Neuropsychiatr Genet, 116B(1), 103-125.
Noble, E. P., Blum, K., Ritchie, T., Montgomery, A., & Sheridan, P. J. (1991). Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry, 48(7), 648-654.
Pohjalainen, T., Rinne, J. O., Nagren, K., Lehikoinen, P., Anttila, K., Syvalahti, E. K., & Hietala, J. (1998). The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry, 3(3), 256-260.
Preisig, M., Bellivier, F., Fenton, B. T., Baud, P., Berney, A., Courtet, P., . . . Malafosse, A. (2000). Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study. Am J Psychiatry, 157(6), 948-955.
Regier, D. A., Farmer, M. E., Rae, D. S., Locke, B. Z., Keith, S. J., Judd, L. L., & Goodwin, F. K. (1990). Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA, 264(19), 2511-2518.
Reich, T., Hinrichs, A., Culverhouse, R., & Bierut, L. (1999). Genetic studies of alcoholism and substance dependence. Am J Hum Genet, 65(3), 599-605.
Ritchie, T., & Noble, E. P. (2003). Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res, 28(1), 73-82.
Sabol, S. Z., Hu, S., & Hamer, D. (1998). A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet, 103(3), 273-279.
Saito, T., Lachman, H. M., Diaz, L., Hallikainen, T., Kauhanen, J., Salonen, J. T., . . . Tiihonen, J. (2002). Analysis of monoamine oxidase A (MAOA) promoter polymorphism in Finnish male alcoholics. Psychiatry Res, 109(2), 113-119.
Shiraishi, H., Suzuki, A., Fukasawa, T., Aoshima, T., Ujiie, Y., Ishii, G., & Otani, K. (2006). Monoamine oxidase A gene promoter polymorphism affects novelty seeking and reward dependence in healthy study participants. Psychiatr Genet, 16(2), 55-58.
Simon, N. M., Otto, M. W., Wisniewski, S. R., Fossey, M., Sagduyu, K., Frank, E., . . . Pollack, M. H. (2004). Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry, 161(12), 2222-2229.
Syagailo, Y. V., Stober, G., Grassle, M., Reimer, E., Knapp, M., Jungkunz, G., . . . Lesch, K. P. (2001). Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders. Am J Med Genet, 105(2), 168-171.
Thompson, J., Thomas, N., Singleton, A., Piggott, M., Lloyd, S., Perry, E. K., . . . Court, J. A. (1997). D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics, 7(6), 479-484.
Wang, T. J., Huang, S. Y., Lin, W. W., Lo, H. Y., Wu, P. L., Wang, Y. S., . . . Lu, R. B. (2007). Possible interaction between MAOA and DRD2 genes associated with antisocial alcoholism among Han Chinese men in Taiwan. Prog Neuropsychopharmacol Biol Psychiatry, 31(1), 108-114.
Westerink, B. H., & de Vries, J. B. (1985). On the origin of dopamine and its metabolite in predominantly noradrenergic innervated brain areas. Brain Res, 330(1), 164-166.
White, H. R., Johnson, V., & Buyske, S. (2000). Parental modeling and parenting behavior effects on offspring alcohol and cigarette use. A growth curve analysis. J Subst Abuse, 12(3), 287-310.
Zhu, Q. S., Grimsby, J., Chen, K., & Shih, J. C. (1992). Promoter organization and activity of human monoamine oxidase (MAO) A and B genes. J Neurosci, 12(11), 4437-4446.
Zuo, Y., Gilbert, D. G., Rabinovich, N. E., Riise, H., Needham, R., & Huggenvik, J. I. (2009). DRD2-related TaqIA polymorphism modulates motivation to smoke. Nicotine Tob Res, 11(11), 1321-1329.