Abstract
Background
GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS.
Methods and results
In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups.
Conclusions
Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.
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References
Yang AC, Tsai SJ (2017) New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci 18:1689. https://doi.org/10.3390/ijms18081689
Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324. https://doi.org/10.1038/nrn1648
Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Joneset EG (1995) Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 52:258–266. https://doi.org/10.1001/archpsyc.1995.03950160008002
Volk D, Austin MC, Pierri J, Sampson A, Lewis D (2001) GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am J Psychiatry 158:256–265. https://doi.org/10.1176/appi.ajp.158.2.256
Rao SG, Williams GV, Goldman-Rakic PS (2000) Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory. J Neurosci 20:485–494. https://doi.org/10.1523/JNEUROSCI.20-01-00485.2000
Addington AM, Gornick M, Duckworth J, Sporn A, Gogtay N, Bobb A, Greenstein D, Lenane M, Gochman P, Baker N, Balkissoon R, Vakkalanka RK, Weinberger DR, Rapoport JL, Straub RE (2005) GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD 67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry 10:581–588. https://doi.org/10.1038/sj.mp.4001599
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. https://doi.org/10.1038/sj.mp.4001988
Elkis H (2007) Treatment-resistant schizophrenia. Psychiatr Clin North Am 30:511–533. https://doi.org/10.1016/j.psc.2007.04.001
Wolkin A, Barouche F, Wolf AP, Rotrosen J, Fowler JS, Shiue CY, Cooper TB, Brodie JD (1989) Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry 146:905–908. https://doi.org/10.1176/ajp.146.7.905
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. https://doi.org/10.1001/archpsyc.1988.01800330013001
Yilmaz Z, Zai CC, Hwang R, Mann S, Arenovich T, Remington G, Daskalakis ZJ (2012) Antipsychotics, dopamine D2 receptor occupancy and clinical improvement in schizophrenia: a meta-analysis. Schizophr Res 140:214–220. https://doi.org/10.1016/j.schres.2012.06.027
Meltzer HY (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17:263–287. https://doi.org/10.1093/schbul/17.2.263
Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. Am J Psychiatry 158:360–369. https://doi.org/10.1176/appi.ajp.158.3.360
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. https://doi.org/10.1016/j.pharmthera.2015.01.005
Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, McGuire PK (2014) Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry 75:e11–e13. https://doi.org/10.1016/j.biopsych.2013.06.011
Mouchlianitis E, Bloomfield MA, Law V, Beck K, Selvaraj S, Rasquinha N, Waldman A, Turkheimer FE, Egerton A, Stone J, Howes OD (2016) Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schizophr Bull 42:744–752. https://doi.org/10.1093/schbul/sbv151
Taylor SF, Tso IF (2015) GABA abnormalities in schizophrenia: a methodological review of in vivo studies. Schizophr Res 167:84–90. https://doi.org/10.1016/j.schres.2014.10.011
de la Fuente-Sandoval C, Reyes-Madrigal F, Mao X, León-Ortiz P, Rodríguez-Mayoral O, Jung-Cook H, Solís-Vivanco R, Graff-Guerrero A, Shungu DC (2018) Prefrontal and striatal gamma-aminobutyric acid levels and the effect of antipsychotic treatment in first-episode psychosis patients. Biol Psychiatry 83:475–483. https://doi.org/10.1016/j.biopsych.2017.09.028
Plevin D, Mohan T, Bastiampillai T (2018) The role of the GABAergic system in catatonia—Insights from clozapine and benzodiazepines. Asian J Psychiatry 32:145–146. https://doi.org/10.1016/j.ajp.2017.12.008
Bojesen KB, Ebdrup BH, Jessen K, Sigvard A, Tangmose K, Edden RAE, Larsson HBW, Rostrup E, Broberg BV, Glenthøj BY (2020) Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis. Psychol Med 50:2182–2193. https://doi.org/10.1017/S0033291719002277
Daskalakis ZJ, George TP (2009) Clozapine, GABA B, and the treatment of resistant schizophrenia. Clin Pharmacol Ther 86:442–446. https://doi.org/10.1038/clpt.2009.115
Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, Orlando Carter Snead 3rd OC (2011) Evidence that clozapine directly interacts on the GABAB receptor. Neuroreport 22: 637-641https://doi.org/10.1097/WNR.0b013e328349739b
Nair PC, McKinnon RA, Miners JO, Bastiampillai T (2020) Binding of clozapine to the GABAB receptor: clinical and structural insights. Mol Psychiatry 25:1910–1919. https://doi.org/10.1038/s41380-020-0709-5
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. https://doi.org/10.1177/0269881107084002
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. https://doi.org/10.1016/j.biopsych.2008.09.012
Kaster TS, de Jesus D, Radhu N, Farzan F, Blumberger DM, Rajji TK, Fitzgerald PB, Daskalakis ZJ (2015) Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia. Schizophr Res 165:157–162. https://doi.org/10.1016/j.schres.2015.04.015
Xu C, Zhang W, Rondard P, Pin JP, Liu J (2014) Complex GABAB receptor complexes: how to generate multiple functionally distinct units from a single receptor. Front Pharmacol 5:12. https://doi.org/10.3389/fphar.2014.00012
Evenseth LSM, Gabrielsen M, Sylte I (2020) The GABAB receptor—structure, ligand binding and drug development. Molecules 25:3093. https://doi.org/10.3390/molecules25133093
Sanzhez-Vives MV, Barbero-Castillo A, Perez-Zabalza M, Reig R (2021) GABAB receptors: modulation of thalamocortical dynamics and synaptic plasticity. Neuroscience 456:131–142. https://doi.org/10.1016/j.neuroscience.2020.03.011
Mizukami K, Sasaki M, Ishikawa M, Iwakiri M, Hidaka S, Shiraishi H, Iritani S (2000) Immunohistochemical localization of gamma-aminobutyric acid(B) receptor in the hippocampus of subjects with schizophrenia. Neurosci Lett 283:101–104. https://doi.org/10.1016/s0304-3940(00)00939-3
Ishikawa M, Mizukami K, Iwakiri M, Asada T (2005) Immunohistochemical and immunoblot analysis of gamma-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder. Neurosci Lett 383:272–277. https://doi.org/10.1016/j.neulet.2005.04.025
Fatemi SH, Folsom TD, Thuras PD (2011) Deficits in GABAB receptor system in schizophrenia and mood disorders: a postmortem study. Schizophr Res 128:37–43. https://doi.org/10.1016/j.schres.2010.12.025
Cherlyn SYT, Woon PS, Liu JJ, Ong WY, Tsai GC, Sim K (2010) Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance. Neurosci Biobehav Rev 34:958–977. https://doi.org/10.1016/j.neubiorev.2010.01.00235
Balan S, Yamada K, Iwayama Y, Hashimoto T, Toyota T, Shimamoto C, Maekawa M, Takagai S, Wakuda T, Kameno Y, Kurita D, Yamada K, Kikuchi M, Hashimoto T, Kanahara N, Yoshikawa T (2017) Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia. Schzophr Res 185:33–40. https://doi.org/10.1016/j.schres.2017.01.003
Zai G, King N, Wong GWH, Barr CL, Kennedy JL (2005) Possible association between the gamma-aminobutyric acid type B receptor (GABBR1) gene and schizophrenia. Eur Neuropsychopharmacol 15:347–352. https://doi.org/10.1016/j.euroneuro.2004.12.006
Zhao X, Qin S, Shi Y, Zhang A, Zhang J, Bian L, Wan C, Feng G, Gu N, Zhang G, He G, Heet L (2007) Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABAB receptor 1 gene and GABAA receptor subunit β2 gene, with schizophrenia using a universal DNA microarray. Schizophr Res 93:374–384. https://doi.org/10.1016/j.schres.2007.02.023
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. https://doi.org/10.1007/s00406-018-0881-7
Lundorf MD, Buttenschøn HN, Foldanger L, Blackwood DHR, Muir WJ, Murray V, Pelosi AJ, Kruse TA, Ewald H, Mors O (2005) Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 135B:94–101. https://doi.org/10.1002/ajmg.b.30137
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. Neuropsychopharmacol 35:1708–1717. https://doi.org/10.1038/npp.2010.35
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. https://doi.org/10.1038/mp.2017.105
Beuten J, Ma JZ, Payne TJ, Dupont RT, Crews KM, Somes G, Williams NJ, Elston RC, Li MD (2005) Single- and multilocus allelic variants within the GABAB receptor subunit2 (GABAB2) gene are significantly associated with nicotine dependence. Am J Hum Genet 76:859–864. https://doi.org/10.1086/429839
Li MD, Mangold JE, Seneviratne C, Chen GB, Ma JZ, Lou XY, Payne TJ (2009) Association and interaction analyses of GABBR1 and GABBR2 with nicotine dependence in European- and African-American populations. PLoS ONE 4:e7055. https://doi.org/10.1371/journal.pone.0007055
Caputo F, Ciminelli BM, Jodice C, Blasi P, Vignoli T, Cibin M, Zoli G, Malaspina P (2017) Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: haplotype frequencies, linkage disequilibrium and association studies. Ann Hum Biol 44:384–388. https://doi.org/10.1080/03014460.2017.1287307
Terranova C, Tucci M, Pietra LD, Ferrara SD (2014) GABA receptors genes polymorphisms and alcohol dependence: no evidence of an association in an Italian male population. Clin Psychopharamacol Neurosci 12:142–148. https://doi.org/10.9758/cpn.2014.12.2.142
Yoo Y, Jung J, Lee YN, Lee Y, Cho H, Na E, Hong JY, Kim E, Lee JS, Lee JS, Hong C, Park SY, Wie J, Miller K, Shur N, Clow C, Ebel RS, DeBrosse SD, Henderson LB, Willaert R, Castaldi C, Tikhonova I, Bilgüvar K, Mane S, Kim KJ, Hwang YS, Lee SG, So I, Lim BC, Choi HJ, Seong JY, Shin YB, Jung H, Chae JH, Choi M (2017) GABBR2 mutations determine phenotype in Rett syndrome and epileptic encephalopathy. Ann Neurol 82:466–478. https://doi.org/10.1002/ana.25032
Vuillaume ML, Jeanne M, Xue L, Blesson S, Denommé-Pichon AS, Alirol S, Brulard C, Colin E, Isidor B, Gilbert-Dussardier B, Odent S, Parent P, Donnart A, Redon R, Bézieau S, Rondard P, Laumonnier F, Toutain A (2018) A novel mutation in the transmembraine 6 domain of GABBR2 leads to a Rett-like phenotype. Ann Neurol 83:437–439. https://doi.org/10.1002/ana.25155
Niu HM, Yang P, Chen HH, Dong SS, Yao S, Chen XF, Yan H, Zhang YJ, Chen YX, Jiang F, Yang TL, Yan GY (2019) Comprehensive functional annotation of susceptibility SNPs prioritized 10 genes for schizophrenia. Transl Psychiatry 9:56. https://doi.org/10.1038/s41398-019-0398-5
Kane JM, Agid O, Baldwin ML, Howes O, Lindenmayer JP, Marder S, Olfson M, Potkin SG, Correll CU (2019) Clinical guideline on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry. https://doi.org/10.4088/JCP.18com12123
Du J, Duan S, Wang H, Chen W, Zhao X, Zhang A, Wang L, Xuan J, Yu L, Wu S, Tang W, Li X, Li H, Feng G, Xing Q, He L (2008) Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia. J Neural Transmit 115:513–519. https://doi.org/10.1007/s00702-0844-z
Acknowledgements
The authors thank Ms. M. Hiruma (Himorogi Psychiatric Institute, Tokyo, Japan) for collecting blood samples from participants.
Funding
This study was supported by a Grant-in-Aid for Scientific Research (21K07476) from the Japan Society for the Promotion of Science (JSPS).
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AM, NK, MK, OI, YW, FY, YN, YO, AH and MI. The first draft of the manuscript was written by AM, NK and SO. All the study process was supervised by MI. All authors read and approved the final manuscript.
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N.K. reports honoraria from Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Janssen Pharmaceutical K.K., Meiji Seika Pharma Co., Ltd., and Mochida Pharmaceutical Co., Ltd. Y.M. received speaker’s honoraria from Pfizer Japan Inc., Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Meiji Seika Pharma Co., Ltd., Eli Lilly Japan K.K., MSD K.K., a subsidiary of Merk and Co., Inc., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., and Sumitomo Dainippon Pharma Co., Ltd. Y.N. reports honoraria from Sumitomo Dainippon Pharma Co., Ltd., and Meiji Seika Pharma Co., Ltd. Y.O. reports honoraria from Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., and Meiji Seika Pharma Co., Ltd. M.I. received consultant fees from Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Pfizer Japan Inc., Abbott Japan Co., Ltd. and Janssen Pharmaceutical K.K., and reports honoraria from Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Eisai Co. Ltd., Daiichi-Sankyo Co. Ltd., Novartis Pharma K.K., Teijin Ltd., Shionogi and Co., Ltd., Hisamitsu Pharmaceutical Co., Inc. and Asahi Kasei Corporation. A.M., M.K., I.O., S.O., F.Y. and A.H. have no conflict of interest to declare.
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Miyazawa, A., Kanahara, N., Kogure, M. et al. A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia. Mol Biol Rep 49, 2015–2024 (2022). https://doi.org/10.1007/s11033-021-07019-z
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DOI: https://doi.org/10.1007/s11033-021-07019-z