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Associations between catechol-O-methyltransferase (COMT) genotypes at rs4818 and rs4680 and gene expression in human dorsolateral prefrontal cortex


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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  1. Arion D, Corradi JP, Tang S et al (2015) Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry 20:1397–1405.

  2. Assicot M, Bohuon C (1971) Presence of two distinct catechol -O- methyltransferase activities in red blood cells. Psychiatry Res 53:871–874

  3. Axelrod J, Tomchick R (1958) Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 233:702–705

  4. Barnett JH, Heron J, Goldman D, Jones PB, Xu K (2009) Effects of catechol-O-methyltransferase on normal variation in the cognitive function of children. Psychiatry Res 166:909–916.

  5. Behl C (2002) Oestrogen as a neuroprotective hormone. Nat Rev Neurosci 3:433–442.

  6. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289–300

  7. Burgoyne RD, Haynes LP (2012) Understanding the physiological roles of the neuronal calcium sensor proteins. Mol Brain 5:2.

  8. Chen J, Song J, Yuan P et al (2011) Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development. J Biol Chem 286:34752–34760.

  9. Clemen CS, Strucksberg K-H, Tangavelou K et al (2010) Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. Brain 133:2920–2941.

  10. Condomines M, Hose D, Reme T et al (2007) Gene expression profiling and real-time pcr analyses make it possible to identify novel potential cancer-testis antigens in multiple myeloma. Blood 110:1793–1793

  11. Dean B, Scarr E (2016) COMT genotype is associated with differential expression of muscarinic M1 receptors in human cortex. Psychiatry Res 171:784–789.

  12. Dean B, Pavey G, Chai SY, Mendelsohn FAO (1999) The localisation and quantification of molecular changes in the human brain using in situ radioligand binding and autoradiography. In: Dean B, Kleinman JE, Hyde TM (eds) Using CNS tissue in psychiatric research: a practical guide. Harwood Academic Press, Amsterdam, pp 67–83

  13. Dean B, Keriakous D, Thomas EA, Scarr E (2005) Understanding the pathology of schizophrenia: the impact of high-throughput screening of the genome and proteome in postmortem CNS. Curr Psychiatry Rev 1:1–9

  14. Dela Peña I, Bang M, Lee J et al (2015) Common prefrontal cortical gene expression profiles between adolescent SHR/NCrl and WKY/NCrl rats which showed inattention behavior. Psychiatry Res 291:268–276.

  15. Diaz-Asper CM, Goldberg TE, Kolachana BS, Straub RE, Egan MF, Weinberger DR (2008) Genetic variation in catechol-O-methyltransferase: effects on working memory in schizophrenic patients, their siblings, and healthy controls. Psychiatry Res 63:72–79.

  16. Dickinson D, Elvevåg B (2009) Genes, cognition and brain through a COMT lens. Neuroscience 164:72–87.

  17. Duman JG, Tu YK, Tolias KF (2016) Emerging roles of BAI adhesion-GPCRs in synapse development and plasticity. Neural Plasticity 2016:8301737.

  18. Egan MF, Goldberg TE, Kolachana BS et al (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98:6917–6922

  19. Ferrer I, Santpere G, Arzberger T et al (2007) Brain protein preservation largely depends on the postmortem storage temperature: implications for study of proteins in human neurologic diseases and management of brain banks: a BrainNet Europe study. J Neuropathol Exp Neurol 66:35–46

  20. Fushan AA, Drayna D, Simons CT, Slack JP (2010) Association between common variation in genes encoding sweet taste signaling components and human sucrose perception. Chem Senses 35:579–592.

  21. Garey LJ (1994) Bordmann's 'Localisation in the cerebral cortex'. Smith-Gordon, London

  22. Gold EB (2011) The timing of the age at which natural menopause occurs. Obstet Gynecol Clin North Am 38:425–440.

  23. Hah N, Danko CG, Core L, Waterfall JJ, Siepel A, Lis JT, Kraus WL (2011) A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 145:622–634.

  24. Heizmann CW (2019) Ca2+-Binding Proteins of the EF-hand superfamily: diagnostic and prognostic biomarkers and novel therapeutic targets. In: Heizmann CW (ed) Calcium-binding proteins of the EF-hand superfamily: from basics to medical applications. Springer, New York, pp 157–186

  25. Hill C, Keks N, Roberts S, Opeskin K, Dean B, Mackinnon A, Copolov D (1996) Problem of diagnosis in postmortem brain studies of schizophrenia. Psychiatry Res 153:533–537

  26. Höök P, Vallee RB (2006) The dynein family at a glance. J Cell Sci 119:4369–4371.

  27. Kingsbury AE, Foster OJ, Nisbet AP et al (1995) Tissue pH as an indicator of mRNA preservation in human post-mortem brain. Brain Res Mol Brain Res 28:311–318

  28. Kippe JM, Mueller TM, Haroutunian V, Meador-Woodruff JH (2015) Abnormal N-Acetylglucosaminyltransferase expression in prefrontal cortex in schizophrenia. Schizophr Res 166:219–224.

  29. Kirst M, Myburg AA, De León JPG, Kirst ME, Scott J, Sederoff R (2004) Coordinated genetic regulation of growth and lignin revealed by quantitative trait locus analysis of cDNA microarray data in an interspecific backcross of eucalyptus. Plant Physiol 135:2368–2378.

  30. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250

  31. Levin ER (2001) Invited Review: Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol 91:1860–1867.

  32. Lilja J, Ivaska J (2018) Integrin activity in neuronal connectivity. J Cell Sci 131:jcs212803.

  33. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Psychiatry Res 34:4202–4210.

  34. Luine VN (2014) Estradiol and cognitive function: past, present and future. Horm Behav 66:602–618.

  35. Maqc Consortium, Shi L, Reid LH, et al. (2006) The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nat Biotechnol 24:1151–1161 Doi: 10.1038/nbt1239

  36. Meyer-Lindenberg A, Nichols T, Callicott JH et al (2006) Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 11:867.

  37. Miranda GG, Rodrigue KM, Kennedy KM (2019) Frontoparietal cortical thickness mediates the effect of COMT Val158Met polymorphism on age-associated executive function. Neurobiol Aging 73:104–114.

  38. Nackley AG, Shabalina SA, Tchivileva IE et al (2006) Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314:1930–1933.

  39. Narayan S, Tang B, Head SR, Gilmartin TJ, Sutcliffe JG, Dean B, Thomas EA (2008) Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res 1239:235–248

  40. Papaleo F, Sannino S, Piras F, Spalletta G (2015) Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia. Eur Neuropsychopharmacol 25:2349–2363.

  41. Parkin GM, Udawela M, Gibbons A, Scarr E, Dean B (2018) 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.

  42. Pawitan Y, Michiels S, Koscielny S, Gusnanto A, Ploner A (2005) False discovery rate, sensitivity and sample size for microarray studies. Psychiatry Res 21:3017–3024.

  43. Philips BJ, Ansell PJ, Newton LG et al (2004) Estrogen receptor-independent catechol estrogen binding activity: protein binding studies in wild-type, estrogen receptor-α KO, and aromatase KO mice tissues. Psychiatry Res 43:6698–6708.

  44. Ramos BP, Arnsten AFT (2007) Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther 113:523–536.

  45. Roberts SB, Hill CA, Dean B, Keks NA, Opeskin K, Copolov DL (1998) Confirmation of the diagnosis of schizophrenia after death using DSM-IV: a victorian experience. Psychiatry Res 32:73–76

  46. Roberts AJ, Kon T, Knight PJ, Sutoh K, Burgess SA (2013) Functions and mechanics of dynein motor proteins. Nat Rev Mol Cell Biol 14:713–726.

  47. Roussos P, Giakoumaki SG, Pavlakis S, Bitsios P (2008) Planning, decision-making and the COMT rs4818 polymorphism in healthy males. Neuropsychologia 46:757–763.

  48. M Sagud L Tudor S Uzun et al 2018 Haplotypic and genotypic association of catechol-O-methyltransferase rs4680 and rs4818 polymorphisms and treatment resistance in schizophrenia. Front Pharmacol 9 10.3389/fphar.2018.00705

  49. Salomoni P (2013) The PML-Interacting protein DAXX: histone loading gets into the picture. Front Oncol 3:152.

  50. Scarr E, Udawela M, Greenough MA et al. (2016) Altered expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cortical homeostasis as part of the pathophysiology of schizophrenia. NPJ Schizophrenia 2 10.1038/npjschz.2016.2

  51. Scarr E, Udawela M, Thomas EA, Dean B (2018) Changed gene expression in subjects with schizophrenia and low cortical muscarinic M1 receptors predicts disrupted upstream pathways interacting with that receptor. Mol Psychiatry 23:295–303.

  52. Scarr E, Udawela M, Dean B (2019) Changed cortical risk gene expression in major depression and shared changes in cortical gene expression between major depression and bipolar disorders. Aust N Z J Psychiatry 53:1189–1198.

  53. Schendzielorz N, Oinas J-P, Myöhänen TT, Reenilä I, Raasmaja A, Männistö PT (2013) Catechol-O-methyltransferase (COMT) protein expression and activity after dopaminergic and noradrenergic lesions of the rat brain. PLoS ONE 8:e61392.

  54. Schott BH, Frischknecht R, Debska-Vielhaber G et al (2010) Membrane-bound catechol-O-methyl transferase in cortical neurons and glial cells is intracellularly oriented. Front Psychiatry 1:142–142.

  55. Schutze N, Vollmer G, Knuppen R (1994) Catecholestrogens are agonists of estrogen receptor dependent gene expression in MCF-7 cells. J Steroid Biochem Mol Biol 48:453–461

  56. Seaman MNJ, Gautreau A, Billadeau DD (2013) Retromer-mediated endosomal protein sorting: all WASHed up! Trends Cell Biol 23:522–528.

  57. Stan AD, Ghose S, Gao XM, Roberts RC, Lewis-Amezcua K, Hatanpaa KJ, Tamminga CA (2006) Human postmortem tissue: what quality markers matter? Brain Res 1123:1–11

  58. Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I (1994) Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 223:1049–1059.

  59. Udawela M, Money TT, Neo J, Seo MS, Scarr E, Dean B, Everall IP (2015) SELENBP1 expression in the prefrontal cortex of subjects with schizophrenia. Trans Psychiatry 5:e615.

  60. Udawela M, Scarr E, Boer S et al (2017) Isoform specific differences in phospholipase C beta 1 expression in the prefrontal cortex in schizophrenia and suicide. NPJ Schizophr 3:19.

  61. Wang K-S, Liu X, Zhang Q, Aragam N, Pan Y (2012) Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder. J Psychiatry Neurosci 37:46–52.

  62. Wang T-M, Shen G-P, Chen M-Y, et al. (2018) Genome-wide association study of susceptibility loci for radiation-induced brain injury. JNCI djy150–djy150 doi: 10.1093/jnci/djy150

  63. Xie T, Ho S-L, Ramsden D (1999) Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 56:31–38.

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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.

Author information

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.

Correspondence to Brian Dean.

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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).

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  • Catechol-O-methyltransferase
  • Dorsolateral prefrontal cortex
  • Gene expression
  • Human postmortem CNS