Abstract
Catechol-O-methyltransferase (COMT) is an enzyme that catalyses the O-methylation, and thereby the inactivation, of catechol-containing molecules. In humans, it has been suggested that COMT modulates cognitive ability, possibly by regulating degradation of dopamine in the prefrontal cortex. Hence, it is significant that two COMT SNPs, rs4680 (c.472 G > A, p.Val158Met) and rs4818 (c.408 C > G), have been associated with cognitive ability in humans. We have shown these SNPs to be associated with levels of muscarinic M1 receptor mRNA in human cortex, which is significant as that receptor also regulates cognitive ability. We decided to determine if COMT genotype was associated with varying levels of COMT protein, as this could be a mechanism by which COMT genotype could be associated with changes in muscarinic M1 receptor mRNA levels. Hence, we measured COMT levels in prefrontal cortex obtained postmortem from 199 subjects, some of whom had a history of schizophrenia, major depressive disorders or bipolar disorders. Our data show, independent of diagnostic status, that genotype at rs4680 and rs4818, but not at rs737865 and rs165599, is associated with differing levels of soluble COMT (S-COMT), but not membrane-bound COMT (MB-COMT). These findings suggest that the association between COMT polymorphisms and cognitive functioning could be, at least in part, due to their association with varying levels of S-COMT. This is important as, unlike MB-COMT, the substrates targeted by S-COMT are likely to be intra-cellular rather than, like dopamine, located mainly in the synaptic vesicles or the extra-cellular space.
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Acknowledgements
The authors would like to thank Mr. Geoff Pavey for careful dissection of the tissue that was used in this study. This project was supported by the National Health and Medical Research Council (NHMRC; Australia; project grant 566967), the Cooperative Research Centre (CRC) for Mental Health and the Victorian Government’s Operational Infrastructure Support Programme. BD is a recipient of NHMRC Fellowship APP1002240, ES was supported by the Australian Research Council (Future Fellowship FT100100689) and GMP is an awardee of an Australian Government Research Training Program Scholarship. The Victorian Brain Bank Network is supported by The Florey Institute of Neuroscience and Mental Health and the Alfred and the Victorian Forensic Institute of Medicine, and funded in part by Parkinson’s Victoria and MND Victoria and Mental Health.
Funding
This project was supported by the National Health and Medical Research Council (NHMRC; Australia; project grant 566967), the Cooperative Research Centre (CRC) for Mental Health and the Victorian Government’s Operational Infrastructure Support Programme. GMP is an awardee of an Australian Government Research Training Program Scholarship.
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Parkin, G.M., Udawela, M., Gibbons, A. et al. Catechol-O-methyltransferase (COMT) genotypes are associated with varying soluble, but not membrane-bound COMT protein in the human prefrontal cortex. J Hum Genet 63, 1251–1258 (2018). https://doi.org/10.1038/s10038-018-0511-2
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DOI: https://doi.org/10.1038/s10038-018-0511-2
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