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Investigating genetic variants for treatment response to selective serotonin reuptake inhibitors in syndromal factors and side effects among patients with depression in Taiwanese Han population

Abstract

Major depressive disorder (MDD) is associated with high heterogeneity in clinical presentation. In addition, response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably among patients. Therefore, identifying genetic variants that may contribute to SSRI treatment responses in MDD is essential. In this study, we analyzed the syndromal factor structures of the Hamilton Depression Rating Scale in 479 patients with MDD by using exploratory factor analysis. All patients were followed up biweekly for 8 weeks. Treatment response was defined for all syndromal factors and total scores. In addition, a genome-wide association study was performed to investigate the treatment outcomes at week 4 and repeatedly assess all visits during follow-up by using mixed models adjusted for age, gender, and population substructure. Moreover, the role of genetic variants in suicidal and sexual side effects was explored, and five syndromal factors for depression were derived: core, insomnia, somatic anxiety, psychomotor-insight, and anorexia. Subsequently, several known genes were mapped to suggestive signals for treatment outcomes, including single-nucleotide polymorphisms (SNPs) in PRF1, UTP20, MGAM, and ENSG00000286536 for psychomotor-insight and in C4orf51 for anorexia. In total, 33 independent SNPs for treatment responses were tested in a mixed model, 12 of which demonstrated a p value <0.05. The most significant SNP was rs2182717 in the ENSR00000803469 gene located on chromosome 6 for the core syndromal factor (β = −0.638, p = 1.8 × 10−4) in terms of symptom improvement over time. Patients with a GG or GA genotype with the rs2182717 SNP also exhibited a treatment response (β = 0.089, p = 2.0 × 10−6) at week 4. Moreover, rs1836075352 was associated with sexual side effects (p = 3.2 × 10−8). Pathway and network analyses using the identified SNPs revealed potential biological functions involved in treatment response, such as neurodevelopment-related functions and immune processes. In conclusion, we identified loci that may affect the clinical response to treatment with antidepressants in the context of empirically defined depressive syndromal factors and side effects among the Taiwanese Han population, thus providing novel biological targets for further investigation.

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Fig. 1: Change in syndromal severity during follow-up.
Fig. 2: The distribution of patients with side effects.

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Data availability

The complete data set of clinical variables is available at https://purl.stanford.edu/bg091gk8548.

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Acknowledgements

We are grateful to all patients for their participation. We thank the physicians and research assistants who contributed to the patient recruitment, data collection, and sample preparation.

Funding

Part of this study was supported by the National Science and Technology Council (NSTC 97-2314-B-400-001-MY3, 100-2314-B-400-002-MY3, 108-2314-B-002-136-MY3, 110-2314-B-002-067-MY3, 111-2410-H-075-003-MY3), the Taipei Veterans General Hospital (V111-C005), and the National Health Research Institutes (NHRI EX106-10627NI, NHRI PH-100-PP-37).

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Contributions

Conceptualization: Y-LL, P-HK, S-JT, and ACY; Methodology: Y-LL, S-SH, M-HS, and P-HK; Software: M-HS; Validation: M-HS and P-HK; Formal analysis: M-HS and S-SH; Investigation: Y-LL, S-JT, and ACY; Resources: Y-LL, S-JT, and P-HK; Data curation: Y-LL and S-JT; Writing—original draft preparation: Y-TC, H-HC, and S-SH; Writing—review and editing: S-SH, H-HC, S-JT, and P-HK; Supervision: S-JT and P-HK.

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Correspondence to Po-Hsiu Kuo.

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Ethical approval

Taiwan National Health Insurance Institutional Review Board (EC0950604) and Taipei Veterans General Hospital Institutional Review Board (2014-06-001B) approved this study. In addition, for investigations involving human subjects, informed consent has been obtained from all the participants.

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Huang, SS., Chen, YT., Su, MH. et al. Investigating genetic variants for treatment response to selective serotonin reuptake inhibitors in syndromal factors and side effects among patients with depression in Taiwanese Han population. Pharmacogenomics J 23, 50–59 (2023). https://doi.org/10.1038/s41397-023-00298-8

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