Importance of the COMT Gene for Sex Differences in Brain Function and Predisposition to Psychiatric Disorders
Importance of the COMT Gene for Sex Differences in Brain Function and Predisposition to Psychiatric Disorders
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DOI：
10.1007/7854_2010_97
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发表时间：
2011-01-01
期刊：
影响因子：
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通讯作者：
Harrison, Paul J.
中科院分区：
文献类型：
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作者：
Tunbridge, Elizabeth M.;Harrison, Paul J.
正如本卷其他地方概述的那样，性别差异会影响大脑功能及其在精神疾病中的功能障碍。众所周知，遗传因素有助于这些性别二态性，但个体基因很少被确定。儿茶酚o -甲基转移酶（COMT）基因编码一种代谢儿茶酚化合物（包括多巴胺）的酶，是这方面的主要候选基因。COMT的酶活性、COMT基因敲除小鼠的神经化学和行为都具有明显的两性二态性。此外，COMT和精神表型之间的遗传关联经常显示出男性和女性之间的差异。虽然许多这些差异是未经证实的或次要的，但有些似乎具有合理的稳健性和重要性，并在本章中进行了回顾。COMT的两性二态效应通常归因于雌激素的转录调节；然而，对文献的仔细研究表明，其他机制可能至少同样重要。在这里，我们回顾了COMT对精神表型和脑功能的两性二态影响的证据，并讨论了可能发生这种情况的潜在机制。我们的结论是，尽管证据不完整，但有越来越多的令人信服的数据表明，COMT对大脑功能及其在精神疾病中的功能障碍具有显着的性别二态效应。虽然COMT的雌激素调节可能是这些性别差异的部分原因，但其他机制也可能参与其中。由于脑功能和精神疾病的遗传结构中的性别差异是规则而不是例外，我们预计将出现更多的证据证明两性二态性，不仅在COMT中，而且在许多其他常染色体基因中。
As outlined elsewhere in this volume, sex differences can affect brain function and its dysfunction in psychiatric disorders. It is known that genetic factors contribute to these sex dimorphisms, but the individual genes have rarely been identified. The catechol-O-methyltransferase (COMT) gene, which encodes an enzyme that metabolises catechol compounds, including dopamine, is a leading candidate in this regard. COMT's enzyme activity, and the neurochemistry and behaviour of COMT knockout mice are both markedly sexually dimorphic. Furthermore, genetic associations between COMT and psychiatric phenotypes frequently show differences between men and women. Although many of these differences are unconfirmed or minor, some appear to be of reasonable robustness and magnitude and are reviewed in this chapter. Sexually dimorphic effects of COMT are usually attributed to transcriptional regulation by oestrogens; however, a careful examination of the literature suggests that additional mechanisms are likely to be at least as important. Here, we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes and brain function, and discuss potential mechanisms by which this may occur. We conclude that despite the evidence being incomplete, there are accumulating and in places compelling data showing that COMT has markedly sexually dimorphic effects on brain function and its dysfunction in psychiatric disorders. Although oestrogenic regulation of COMT is probably partially responsible for these sex differences, other mechanisms are likely also involved. Since sex differences in the genetic architecture of brain function and psychiatric disorders are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.