Atsuhiro Miyazawa1, Nobuhisa Kanahara2,3, Masanobu Kogure1, Ikuo Otsuka4, Satoshi Okazaki4, Yoshinori Watanabe5, Fumiaki Yamasaki1, Yusuke Nakata1, Yasunori Oda1, Akitoyo Hishimoto6, Masaomi Iyo1. 1. Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. 2. Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. kanahara@faculty.chiba-u.jp. 3. Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba-shi, Chiba, 260-8670, Japan. kanahara@faculty.chiba-u.jp. 4. Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan. 5. Himorogi Psychiatric Institute, Tokyo, Japan. 6. Department of Psychiatry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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.
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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