Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

Masanobu Kogure; Nobuhisa Kanahara; Atsuhiro Miyazawa; Yuki Shiko; Ikuo Otsuka; Koichi Matsuyama; Masayuki Takase; Makoto Kimura; Hiroshi Kimura; Kiyomitsu Ota; Keita Idemoto; Masaki Tamura; Yasunori Oda; Taisuke Yoshida; Satoshi Okazaki; Fumiaki Yamasaki; Yusuke Nakata; Yoshinori Watanabe; Tomihisa Niitsu; Akitoyo Hishimoto; Masaomi Iyo

doi:10.3389/fpsyt.2023.1334335

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

Front Psychiatry. 2024 Feb 27:14:1334335. doi: 10.3389/fpsyt.2023.1334335. eCollection 2023.

Authors

Masanobu Kogure¹, Nobuhisa Kanahara², Atsuhiro Miyazawa^{1

3}, Yuki Shiko⁴, Ikuo Otsuka⁵, Koichi Matsuyama^{1

6}, Masayuki Takase⁷, Makoto Kimura^{8

9}, Hiroshi Kimura^{1

10

11}, Kiyomitsu Ota^{3

12}, Keita Idemoto^{1

3}, Masaki Tamura^{3

13}, Yasunori Oda¹, Taisuke Yoshida³, Satoshi Okazaki⁵, Fumiaki Yamasaki¹, Yusuke Nakata¹, Yoshinori Watanabe¹⁴, Tomihisa Niitsu¹, Akitoyo Hishimoto⁵, Masaomi Iyo¹

Affiliations

¹ Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
² Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan.
³ Doujin-kai Kisarazu Hospital, Kisarazu, Japan.
⁴ Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan.
⁵ Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.
⁶ Douwa-kai Chiba Hospital, Funabashi, Japan.
⁷ Shoushin-kai Mobara Mental Hospital, Mobara, Japan.
⁸ Chiba Psychiatric Medical Center, Chiba, Japan.
⁹ Department of Psychiatry, Kameda Medical Center, Kamogawa, Japan.
¹⁰ Gakuji-kai Kimura Hospital, Chiba, Japan.
¹¹ Department of Psychiatry, School of Medicine, International University of Health and Welfare, Narita, Japan.
¹² Choshi-kokoro Clinic, Choshi, Japan.
¹³ Department of Cognitive Behavioral Psychology, Chiba University Graduate School of Medicine, Chiba, Japan.
¹⁴ Himorogi Psychiatric Institute, Tokyo, Japan.

Abstract

Background: Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways.

Patients and methods: To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489).

Results: The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology.

Conclusion: The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

Keywords: antipsychotic; dopamine; psychosis; single nucleotide polymorphism; variable number of tandem repeats.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a Grant-in-Aid for Scientific Research (21K07476, NK) from the Japan Society for the Promotion of Science (JSPS), and also supported by a Grand (MKo) from the Osaka Medical Foundation for Intractable Diseases grant no. (28-2-10).