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, Michiaki Kubo, L. Wang, R. Kaddurah-Daouk, R. M. Weinshilboum

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1717-1725
Number of pages9
JournalMolecular Psychiatry
Volume21
Issue number12
DOIs
Publication statusPublished - 01-12-2016

Fingerprint

Pharmacogenetics
Major Depressive Disorder
Serotonin Uptake Inhibitors
Serotonin
Single Nucleotide Polymorphism
Genome-Wide Association Study
Citalopram
Chromosomes
Genome
Chromosomes, Human, Pair 5
Metabolomics
Quantitative Trait Loci
Proteasome Endopeptidase Complex
Neuroblastoma
Research
Genes
Phenotype
Cell Line
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

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. Molecular Psychiatry, 21(12), 1717-1725. https://doi.org/10.1038/mp.2016.6
Gupta, M. ; Neavin, D. ; Liu, D. ; Biernacka, J. ; Hall-Flavin, D. ; Bobo, W. V. ; Frye, M. A. ; Skime, M. ; Jenkins, G. D. ; Batzler, A. ; Kalari, K. ; Matson, W. ; Bhasin, S. S. ; Zhu, H. ; Mushiroda, T. ; Nakamura, Y. ; Kubo, Michiaki ; Wang, L. ; Kaddurah-Daouk, R. ; Weinshilboum, R. M. / TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder : Pharmacometabolomics-informed pharmacogenomics. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 12. pp. 1717-1725.
@article{6c090d8c084046fa95b519616c6ac2e5,
title = "TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: Pharmacometabolomics-informed pharmacogenomics",
abstract = "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.",
author = "M. Gupta and D. Neavin and D. Liu and J. Biernacka and D. Hall-Flavin and Bobo, {W. V.} and Frye, {M. A.} and M. Skime and Jenkins, {G. D.} and A. Batzler and K. Kalari and W. Matson and Bhasin, {S. S.} and H. Zhu and T. Mushiroda and Y. Nakamura and Michiaki Kubo and L. Wang and R. Kaddurah-Daouk and Weinshilboum, {R. M.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1038/mp.2016.6",
language = "English",
volume = "21",
pages = "1717--1725",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "12",

}

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 2016, 'TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: Pharmacometabolomics-informed pharmacogenomics', Molecular Psychiatry, vol. 21, no. 12, pp. 1717-1725. https://doi.org/10.1038/mp.2016.6

TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder : Pharmacometabolomics-informed pharmacogenomics. / Gupta, M.; Neavin, D.; Liu, D.; Biernacka, J.; Hall-Flavin, D.; Bobo, W. V.; Frye, M. A.; Skime, M.; Jenkins, G. D.; Batzler, A.; Kalari, K.; Matson, W.; Bhasin, S. S.; Zhu, H.; Mushiroda, T.; Nakamura, Y.; Kubo, Michiaki; Wang, L.; Kaddurah-Daouk, R.; Weinshilboum, R. M.

In: Molecular Psychiatry, Vol. 21, No. 12, 01.12.2016, p. 1717-1725.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder

T2 - Pharmacometabolomics-informed pharmacogenomics

AU - Gupta, M.

AU - Neavin, D.

AU - Liu, D.

AU - Biernacka, J.

AU - Hall-Flavin, D.

AU - Bobo, W. V.

AU - Frye, M. A.

AU - Skime, M.

AU - Jenkins, G. D.

AU - Batzler, A.

AU - Kalari, K.

AU - Matson, W.

AU - Bhasin, S. S.

AU - Zhu, H.

AU - Mushiroda, T.

AU - Nakamura, Y.

AU - Kubo, Michiaki

AU - Wang, L.

AU - Kaddurah-Daouk, R.

AU - Weinshilboum, R. M.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84959121708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959121708&partnerID=8YFLogxK

U2 - 10.1038/mp.2016.6

DO - 10.1038/mp.2016.6

M3 - Article

C2 - 26903268

AN - SCOPUS:84959121708

VL - 21

SP - 1717

EP - 1725

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 12

ER -