Lappalainen J, Long J C, Virkkunen M, Ozaki N, Goldman D, Linnoila M
Section of Population Genetics and Linkage, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852, USA.
Biol Psychiatry. 1999 Sep 15;46(6):821-6. doi: 10.1016/s0006-3223(98)00361-8.
Heritable variation in brain monoaminergic activity has been suggested to lead to interindividual differences in vulnerability to alcoholism, and many other behavioral disorders. We evaluated if a functional Cys23Ser polymorphism in the 5-HT2C receptor gene, the principal serotonin receptor in the brain, contributes to variation in serotonin, norepinephrine and dopamine activity, as indexed by their major metabolite concentrations in cerebrospinal fluid (CSF). Genotype-monoamine metabolite concentration associations were subsequently correlated to risk for alcoholism.
The study sample consisted of unrelated Finnish males, including 214 alcoholic, violent offenders and 222 population controls who were interviewed using the Structured Clinical Interview for DSM-III-R, blind rated for psychiatric diagnoses and typed for the HTR2C Cys23Ser polymorphism. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), the major metabolite of norepinephrine, and homovanillic acid (HVA), the major metabolite of dopamine were available from 195 individuals.
The major finding in this study was that HTR2C CysSer23 significantly contributed to CSF MHPG concentrations (p = .012). Higher concentrations of CSF MHPG were observed both in alcoholic violent offenders and population controls with HTR2C Ser23 genotype. Despite the association of Cys23Ser to CSF MHPG, HTR2C genotype was not associated with alcoholism, nor with other psychiatric disorders present in this sample.
We conclude that a functional HTR2C Cys23Ser polymorphism contributes to the interindividual genetic variation of CSF MHPG explaining 3% of the total variance. This finding suggests that 5-HT2C receptors are involved in the regulation of norepinephrine turnover in humans; however, HTR2C Cys23Ser does not appear to contribute to the risk of alcoholism, or its contribution to this complex and heterogenous disorder is too small to be detected by a sample of this size and structure.
有研究表明，大脑单胺能活性的遗传变异会导致个体对酒精成瘾及许多其他行为障碍的易感性存在差异。我们评估了大脑主要血清素受体5-HT2C受体基因中的功能性Cys23Ser多态性是否会导致血清素、去甲肾上腺素和多巴胺活性的变化，这些变化通过它们在脑脊液（CSF）中的主要代谢物浓度来衡量。随后，将基因型与单胺代谢物浓度的关联与酒精成瘾风险进行了相关性分析。
研究样本包括无血缘关系的芬兰男性，其中有214名酒精成瘾、有暴力行为的罪犯以及222名普通对照者。使用针对DSM-III-R的结构化临床访谈对他们进行访谈，由盲人对精神疾病诊断进行评分，并对HTR2C Cys23Ser多态性进行分型。195名个体提供了脑脊液中血清素的主要代谢物5-羟吲哚乙酸（5-HIAA）、去甲肾上腺素的主要代谢物3-甲氧基-4-羟基苯乙二醇（MHPG）以及多巴胺的主要代谢物高香草酸（HVA）的浓度数据。
本研究的主要发现是，HTR2C CysSer23显著影响脑脊液中MHPG的浓度（p = 0.012）。在具有HTR2C Ser23基因型的酒精成瘾暴力罪犯和普通对照者中，均观察到脑脊液中MHPG浓度较高。尽管Cys23Ser与脑脊液中MHPG有关联，但HTR2C基因型与酒精成瘾以及本样本中存在的其他精神疾病均无关联。
我们得出结论，功能性HTR2C Cys23Ser多态性导致脑脊液中MHPG的个体间遗传变异，解释了总变异的3%。这一发现表明5-HT2C受体参与了人类去甲肾上腺素周转的调节；然而，HTR2C Cys23Ser似乎对酒精成瘾风险没有影响，或者其对这种复杂的异质性疾病的影响太小，以至于在这个规模和结构的样本中无法检测到。
