TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: Pharmacometabolomics-informed pharmacogenomics

M. Gupta, D. Neavin, D. Liu, J. Biernacka, D. Hall-Flavin, W. V. Bobo, M. A. Frye, M. Skime, G. D. Jenkins, A. Batzler, K. Kalari, W. Matson, S. S. Bhasin, H. Zhu, T. Mushiroda, Y. Nakamura, M. Kubo, L. Wang, R. Kaddurah-Daouk, R. M. Weinshilboum

研究成果: Article査読

69 被引用数 (Scopus)


Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.

ジャーナルMolecular Psychiatry
出版ステータスPublished - 01-12-2016

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 細胞および分子神経科学
  • 精神医学および精神衛生


「TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: Pharmacometabolomics-informed pharmacogenomics」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。