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Interacting Roles of COMT and GAD1 Genes in Patients with Treatment-Resistant Schizophrenia: a Genetic Association Study of Schizophrenia Patients and Healthy Controls

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Abstract

The projection from dopaminergic neurons to gamma-aminobutyric acid (GABA) interneurons in the prefrontal cortex is involved in the etiology of schizophrenia. The impact of interacting effects between dopamine signals and the expression of GABA on the clinical phenotypes of schizophrenia has not been studied. Since these interactions could be closely involved in prefrontal cortex functions, patients with specific alleles of these relevant molecules (which lead to lower or vulnerable genetic functions) may develop treatment-refractory symptoms. We conducted a genetic association study focusing on COMT and GAD1 genes for a treatment-resistant schizophrenia (TRS) group (n=171), a non-TRS group (n=592), and healthy controls (HC: n=447), and we examined allelic combinations specific to TRS. The results revealed that the percentage of subjects with Met allele of rs4680 on the COMT gene and C/C homozygote of rs3470934 on the GAD1 gene was significantly higher in the TRS group than the other two groups. There was no significant difference between the non-TRS group and HC groups. Considering the direction of functions of these single-nucleotide polymorphisms revealed by previous studies, we speculate that subjects with the Met/CC allelic combination could have a higher dopamine level and a lower expression of GABA in the prefrontal cortex. Our results suggest that an interaction between the dopaminergic signal and GABA signal intensities could differ between TRS patients and patients with other types of schizophrenia and healthy subjects.

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References

  • Apud JA, Weinberger DR (2007) Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors. CNS Drugs 21:535–557

    Article  CAS  PubMed  Google Scholar 

  • Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K (1997) Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A 94:6496–6499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnett JH, Jones PB, Robbins TW, Müller U (2007) Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry 12:502–509

    Article  CAS  PubMed  Google Scholar 

  • Buchanan RW (2007) Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull 33:1013–1022

    Article  PubMed  Google Scholar 

  • Buzsáki G, Geisler C, Henze DA, Wang XJ (2004) Interneuron Diversity series: circuit complexity and axon wiring economy of cortical interneurons. Trends Neurosci 27:186–193

    Article  PubMed  Google Scholar 

  • Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Condie BG, Bain G, Gottlieb DI, Capecchi MR (1997) Cleft palate in mice with a targeted mutation in the gamma-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67. Proc Natl Acad Sci U S A 94:11451–11455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Bartolomeis A, Prinzivalli E, Callovini P, D’Ambrosio L, Altavilla B, Avagliano C, Iasevoli F (2018) Treatment resistant schizophrenia and neurological soft signs may converge on the same pathology: evidence from explanatory analysis on clinical, psychopathological and cognitive variables. Progress in Neuropsychopharmacology and Biological Psychiatry 81:356–366

    Article  Google Scholar 

  • Daskalakis ZJ, Christensen BK, Fitzgerald PB, Moller B, Fountain SI, Chen R (2008) Increased cortical inhibition in persons with schizophrenia treated with clozapine. J Psychopharmacol 22:203–209

    Article  CAS  PubMed  Google Scholar 

  • Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD (2012) Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 169:1203–1210

    Article  PubMed  Google Scholar 

  • Elkis H (2007) Treatment-resistant schizophrenia. Psychiatr Clin North Am 30: 511–533. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Google Scholar 

  • Fries P, Neuenschwander S, Engel AK, Goebel R, Singer W (2001) Rapid feature selective neuronal synchronization through correlated latency shifting. Nat Neurosci 4:194–200

    Article  CAS  PubMed  Google Scholar 

  • Frydecka D, Beszłej JA, Gościmski P, Kiejna A, Misiak B (2016) Profiling cognitive impairment in treatment-resistant schizophrenia patients. Psychiatry Research 235:133–138

    Article  PubMed  Google Scholar 

  • Goldstein ME, Anderson VM, Pillai A, Kydd RR, Russell BR (2015) Glutamatergic neurometabolites in clozapine-responsive and -resistant schizophrenia. Int J Neuropsychopharmacol 18:pyu117

  • Hajj A, Obeid S, Sahyoun S, Haddad C, Azar J, Rabbaa Khabbaz L, Hallit S (2019) Clinical and genetic factors associated with resistance to treatment in patients with schizophrenia: a case-control study. Int J Mol Sci 20:4753

    Article  CAS  PubMed Central  Google Scholar 

  • Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562

    Article  PubMed  PubMed Central  Google Scholar 

  • Ikeda M, Ozaki N, Yamanouchi Y, Suzuki T, Kitajima T, Kinoshita Y, Inada T, Iwata N (2007) No association between the glutamate decarboxylase 67 gene (GAD1) and schizophrenia in the Japanese population. Schizophr Res 91:22–26

    Article  PubMed  Google Scholar 

  • Inada T, Nakamura A, Iijima Y (2003) Relationship between catechol-O-methyltransferase polymorphism and treatment-resistant schizophrenia. Am J Med Genet B Neuropsychiatr Genet 120B(1):35–39

    Article  PubMed  Google Scholar 

  • Ira E, Zanoni M, Ruggeri M, Dazzan P, Tosato S (2013) COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. 38(6):366-80. https://doi.org/10.1503/jpn.120178

  • Iwata Y, Nakajima S, Plitman E, Caravaggio F, Kim J, Shah P, Mar W, Chavez S, De Luca V, Mimura M, Remington G, Gerretsen P, Graff-Guerrero A (2019) Glutamatergic neurometabolite levels in patients with ultra-treatment-resistant schizophrenia: a cross-sectional 3T proton magnetic resonance spectroscopy study. Biol Psychiatry 85:596–605

    Article  CAS  PubMed  Google Scholar 

  • Joober R, Rouleau GA, Lal S, Dixon M, O’Driscoll G, Palmour R, Annable L, Bloom D, Lalonde P, Labelle A, Benkelfat C (2002) Neuropsychological impairments in neuroleptic-responder vs. -nonresponder schizophrenic patients and healthy volunteers. Schizophrenia Research 53:229–238

    Article  PubMed  Google Scholar 

  • Käenmäki M, Tammimäki A, Myöhänen T, Pakarinen K, Amberg C, Karayiorgou M, Gogos JA, Männistö PT (2010) Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice. J Neurochem 114:1745–1755

    Article  PubMed  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

  • Kaster TS, de Jesus D, Radhu N, Farzan F, Blumberger DM, Rajji TK, Fitzgerald FB, Daskalakis ZJ (2015) Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia. Schizophr Res 165:157–162

    Article  PubMed  Google Scholar 

  • Kim E, Howes OD, Veronese M, Beck K, Seo S, Park JW, Lee JS, Lee YS, Kwon JS (2017) Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: an [(18)F]DOPA PET study. Neuropsychopharmacology 42:941–950

    Article  CAS  PubMed  Google Scholar 

  • Kirenskaya AV, Storozheva ZI, Gruden MA, Sewell RDE (2018) COMT and GAD1 gene polymorphisms are associated with impaired antisaccade task performance in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 268:571–584

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A (2001) Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 432:119–136

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Gonzalez-Burgos G (2006) Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12:1016–1022

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D (2008) Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry 165:1585–1593

    Article  PubMed  PubMed Central  Google Scholar 

  • Lidow MS, Williams GV, Goldman-Rakic PS (1998) The cerebral cortex: a case for a common site of action of antipsychotics. Trends Pharmacol Sci 19:136–140

    Article  CAS  PubMed  Google Scholar 

  • Liu SK, Fitzgerald PB, Daigle M, Chen R, Daskalakis ZJ (2009) The relationship between cortical inhibition, antipsychotic treatment, and the symptoms of schizophrenia. Biol Psychiatry 65:503–509

    Article  PubMed  Google Scholar 

  • Marenco S, Savostyanova AA, van der Veen JW, Geramita M, Stern A, Barnett AS, Kolachana B, Radulescu E, Zhang F, Callicott JH, Straub RE, Shen J, Weinberger DR (2010) Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT. Neuropsychopharmacology 35:1708–1717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCutcheon RA, Krystal JH, Howes OD (2020) Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry 19:15–33

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitchell AC, Jiang Y, Peter C, Akbarian S (2015) Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. Schizophr Res 167:28–34

    Article  PubMed  Google Scholar 

  • Miyazawa A, Kanahara K, Nakata Y, Kodama S, Kimura H, Kimura A, Oda Y, Watanabe H, Iyo M (2021) Clozapine prolongs cortical silent period in patients with treatment-resistant schizophrenia. Psychophrmacol Bull In Press

  • Momiyama T, Nishijo T (2017) Dopamine and serotonin-induced modulation of GABAergic and glutamatergic transmission in the striatum and basal forebrain. Front Neuroanat 11:42

    Article  PubMed  PubMed Central  Google Scholar 

  • Nakata Y, Kanahara N, Kimura A, Niitsu T, Komatsu H, Oda Y, Ishikawa M, Hasegawa T, Kamata Y, Yamauchi A, Inazumi K, Kimura H, Iyo M (2020) Autistic traits and cognitive profiles of treatment-resistant schizophrenia. Schizophr Res Cogn 22:100186

  • Nogueira NGHM, Bacelar MFB, Ferreira BP, Parma JO, Lage GM (2019) Association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and motor behavior in healthy adults: a study review. Brain Res Bull 144:223–232

    Article  CAS  PubMed  Google Scholar 

  • O’Connor WT, O’Shea SD (2015) Clozapine and GABA transmission in schizophrenia disease models: establishing principles to guide treatments. Pharmacol Ther 150:47–80

    Article  CAS  PubMed  Google Scholar 

  • Oishi K, Kanahara N, Takase M, Oda Y, Nakata Y, Niitsu T, Ishikawa M, Sato Y, Iyo M (2018) Vulnerable combinations of functional dopaminergic polymorphisms to late-onset treatment resistant schizophrenia. PLoS One 13: e0207133

  • Oishi K, Niitsu T, Kanahara N, Hashimoto T, Komatsu H, Sasaki T, Takase M, Sato Y, Iyo M (2020) Genetic combination risk for schizophrenia. Schizophr Research 215:473–474

    Article  Google Scholar 

  • Okochi T, Ikeda M, Kishi T, Kawashima K, Kinoshita Y, Kitajima T, Yamanouchi Y, Tomita M, Inada T, Ozaki N, Iwata N (2009) Meta-analysis of association between genetic variants in COMT and schizophrenia: an update. Schizophr Res 110:140–148

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Pigoni A, Lazzaretti M, Mandolini GM, Delvecchio G, Altamura AC, Soares JC, Brambilla P (2019) The impact of COMT polymorphisms on cognition in bipolar disorder: a review. J Affect Dis 243:545–551

    Article  CAS  PubMed  Google Scholar 

  • Sagud M, Tudor L, Uzun S, Perkovic MN, Zivkovic M, Konjevod M, Kozumplik O, Cusa BV, Strac DS, Rados I, Mimica N, Peles AM, Erjavec GN, Pivac N (2018) Haplotypic and genotypic association of catechol-O-methyltransferase rs4680 and rs4818 polymorphisms and treatment resistance in schizophrenia. Front Pharmacol 9:705

    Article  PubMed  PubMed Central  Google Scholar 

  • Sannino S, Gozzi A, Cerasa A, Piras F, Scheggia D, Manago F, Damiano M, Galbusera A, Erickson LC, De Pietri Tonelli D, Bifone A, Tsaftaris SA, Caltagirone C, Weinberger DR, Spalletta G, Papaleo F (2020) COMT genetic reduction produces sexually divergent effects on cortical anatomy and working memory in mice and humans. Cereb Cortex 25:2529–2541

    Article  Google Scholar 

  • Schaefer J, Giangrande E, Weinberger DR, Dickinson D (2013) The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophr Res 150:42–50

    Article  PubMed  PubMed Central  Google Scholar 

  • Schwartz TL, Sachdeva S, Stahl SM (2012) Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Front Pharmacol 3:195

    Article  PubMed  PubMed Central  Google Scholar 

  • Shukla AA, Jha M, Birchfield T, Mukherjee S, Gleason K, Abdisalaam S, Asaithamby A, Adams-Huet B, Tamminga CA, Ghose S (2016) COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: differences in controls and in schizophrenia. Schizophr Res 173:94–100

    Article  PubMed  PubMed Central  Google Scholar 

  • Sohal VS, Rubenstein JLR (2019) Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry 24:1248–1257

    Article  PubMed  PubMed Central  Google Scholar 

  • Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB, Vakkalanka RK, Kolachana BS, Kleinman JE, Weinberger DR (2007) Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry 12:854–869

    Article  CAS  PubMed  Google Scholar 

  • Tallon-Baudry C, Bertrand O, Peronnet F, Pernier J (1998) Induced gamma-band activity during the delay of a visual short-term memory task in humans. J Neurosci 18:4244–4254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tao R, Davis KN, Li C, Shin JH, Gao Y, Jaffe AE, Gondré-Lewis MC, Weinberger DR, Kleinman JE, Hyde TM (2018) GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia. Mol Psychiatry 23:1496–1505

    Article  CAS  PubMed  Google Scholar 

  • Terzić T, Kastelic M, Dolžan V, Plesničar BK (2016) Genetic polymorphisms in dopaminergic system and treatment-resistant schizophrenia. Psychiatr Danub 28:127–131

    PubMed  Google Scholar 

  • Tsuchimine S, Yasui-Furukori N, Kaneda A, Kaneko S (2013) Differential effects of the catechol-O-methyltransferase Val158Met genotype on the cognitive function of schizophrenia patients and healthy Japanese individuals. PLoS One 8: e76763

  • Varju P, Katarova Z, Madarász E, Szabó G (2002) Sequential induction of embryonic and adult forms of glutamic acid decarboxylase during in vitro-induced neurogenesis in cloned neuroectodermal cell-line, NE-7C2. J Neurochem 80:605–615

    Article  CAS  PubMed  Google Scholar 

  • Wu S, Upadhyay N, Lu J, Jiang X, Li S, Qing Z, Wang J, Liang X, Zhang X, Zhang B (2020) Interaction of catechol-O-methyltransferase Val158Met polymorphism and sex influences association of parietal intrinsic functional connectivity and immediate verbal memory. Brain Behav 10: e01784

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Authors and Affiliations

  1. Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan

    Masanobu Kogure, Nobuhisa Kanahara, Atsuhiro Miyazawa, Kengo Oishi, Yusuke Nakata, Yasunori Oda & Masaomi Iyo

  2. Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan

    Nobuhisa Kanahara

  3. Doujin-kai Kisarazu Hospital, Chiba, Japan

    Atsuhiro Miyazawa

  4. Department of Cyclic Innovation, Japan Agency for Medical Research Development, Tokyo, Japan

    Kengo Oishi

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  1. Masanobu Kogure
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  2. Nobuhisa Kanahara
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  3. Atsuhiro Miyazawa
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  4. Kengo Oishi
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  5. Yusuke Nakata
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Correspondence to Nobuhisa Kanahara.

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Kogure, M., Kanahara, N., Miyazawa, A. et al. Interacting Roles of COMT and GAD1 Genes in Patients with Treatment-Resistant Schizophrenia: a Genetic Association Study of Schizophrenia Patients and Healthy Controls. J Mol Neurosci 71, 2575–2582 (2021). https://doi.org/10.1007/s12031-021-01866-y

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