Abstract
Having reported associations between catechol-O-methyltransferase (COMT) genotypes at SNPs rs4818 and rs4680 with levels of soluble COMT (S-COMT) in human dorsolateral prefrontal cortex (DLPFC), we postulated that changes in the levels of cortical S-COMT could impact on behavioural abilities associated with COMT genotype through S-COMT-mediated changes in gene expression. To test this hypothesis, we have examined the relationships between COMT genotypes and gene expression measured using the Affymetrix™ Human Exon 1.0 ST Array in the DLPFC from 141 individuals, some of whom had had a psychiatric disorder. There were significant differences in levels of expression of 15 genes between individuals with a homozygous genotype at rs4818 (GG vs CC), compared to differences in levels of expression of 6 genes between homozygotes at rs4680 (GG vs AA); levels of expression of CEP128, EFCAB13, and FAM133A differed between homozygotes at both SNPs. Fourteen of the genes differentially expressed in the DLPFC according to COMT genotypes have oestrogen receptor elements and their expression could, therefore, be regulated by catecholestrogens, which are substrates for COMT that occupy and activate oestrogen receptors. In addition, the changes in gene expression between the homozygotes at rs4818 or rs4680 would be expected to impact on neuronal function, synaptic plasticity, cognition, and attention. These data would support a hypothesis that the mechanism underlying the association between COMT genotype and cognition involves differential changes in cortical gene expression.
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Acknowledgements
The authors would like to thank Dr Madhara Udawela and Mr Geoffrey Pavey for preparing the high-quality RNA from human cortex that was used in this study. This research was funded in part by the National Health and Medical Research Council (NHMRC; Australia; project grant 566967), the Cooperative Research Centre (CRC) for Mental Health, the Australian Government Research Training Program Scholarship (GMP), and the Victorian Government’s Operational Infrastructure Support Programme.
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All authors contributed to the study conception and design. The curation of the COMT genotyping data in this study was by Georgia Parkin. The data analysis for this study was performed by Brian Dean who also prepared the first draft of the manuscript. All authors commented on the first and subsequent drafts of the manuscript. All authors read and approved the final manuscript.
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Dean, B., Parkin, G.M. & Gibbons, A.S. Associations between catechol-O-methyltransferase (COMT) genotypes at rs4818 and rs4680 and gene expression in human dorsolateral prefrontal cortex. Exp Brain Res 238, 477–486 (2020). https://doi.org/10.1007/s00221-020-05730-0
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DOI: https://doi.org/10.1007/s00221-020-05730-0