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

Publication ,  Journal Article
Gupta, M; Neavin, D; Liu, D; Biernacka, J; Hall-Flavin, D; Bobo, WV; Frye, MA; Skime, M; Jenkins, GD; Batzler, A; Kalari, K; Matson, W ...
Published in: Mol Psychiatry
December 2016

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.

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Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

December 2016

Volume

21

Issue

12

Start / End Page

1717 / 1725

Location

England

Related Subject Headings

  • Treatment Outcome
  • Tetraspanins
  • Serotonin
  • Selective Serotonin Reuptake Inhibitors
  • Psychiatry
  • Polymorphism, Single Nucleotide
  • Pharmacogenetics
  • Metabolomics
  • Male
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gupta, M., Neavin, D., Liu, D., Biernacka, J., Hall-Flavin, D., Bobo, W. V., … Weinshilboum, R. M. (2016). TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Mol Psychiatry, 21(12), 1717–1725. https://doi.org/10.1038/mp.2016.6
Gupta, M., D. Neavin, D. Liu, J. Biernacka, D. Hall-Flavin, W. V. Bobo, M. A. Frye, et al. “TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.Mol Psychiatry 21, no. 12 (December 2016): 1717–25. https://doi.org/10.1038/mp.2016.6.
Gupta M, Neavin D, Liu D, Biernacka J, Hall-Flavin D, Bobo WV, et al. TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Mol Psychiatry. 2016 Dec;21(12):1717–25.
Gupta, M., et al. “TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.Mol Psychiatry, vol. 21, no. 12, Dec. 2016, pp. 1717–25. Pubmed, doi:10.1038/mp.2016.6.
Gupta M, Neavin D, Liu D, Biernacka J, Hall-Flavin D, Bobo WV, Frye MA, Skime M, Jenkins GD, Batzler A, Kalari K, Matson W, Bhasin SS, Zhu H, Mushiroda T, Nakamura Y, Kubo M, Wang L, Kaddurah-Daouk R, Weinshilboum RM. TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Mol Psychiatry. 2016 Dec;21(12):1717–1725.

Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

December 2016

Volume

21

Issue

12

Start / End Page

1717 / 1725

Location

England

Related Subject Headings

  • Treatment Outcome
  • Tetraspanins
  • Serotonin
  • Selective Serotonin Reuptake Inhibitors
  • Psychiatry
  • Polymorphism, Single Nucleotide
  • Pharmacogenetics
  • Metabolomics
  • Male
  • Humans