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
Shiau-Shian Huang, Yi-Ting Chen, Mei-Hsin Su, Shih-Jen Tsai, Hsi-Han Chen, Albert C. Yang, Yu-Li Liu, Po-Hsiu Kuo
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引用次数: 1
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.
期刊介绍:
The Pharmacogenomics Journal is a print and electronic journal, which is dedicated to the rapid publication of original research on pharmacogenomics and its clinical applications.
Key areas of coverage include:
Personalized medicine
Effects of genetic variability on drug toxicity and efficacy
Identification and functional characterization of polymorphisms relevant to drug action
Pharmacodynamic and pharmacokinetic variations and drug efficacy
Integration of new developments in the genome project and proteomics into clinical medicine, pharmacology, and therapeutics
Clinical applications of genomic science
Identification of novel genomic targets for drug development
Potential benefits of pharmacogenomics.