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.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Neavin
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Biomedical Statistics and Bioinformatics - Genetics and Bioinformatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Biernacka
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hall-Flavin
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: W V
authors.initials: WV
authors.lastname: Bobo
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Skime
authors.affiliation: Department of Biomedical Statistics and Bioinformatics - Genetics and Bioinformatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Jenkins
authors.affiliation: Department of Biomedical Statistics and Bioinformatics - Genetics and Bioinformatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Batzler
authors.affiliation: Department of Biomedical Statistics and Bioinformatics - Genetics and Bioinformatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kalari
authors.affiliation: Bedford VA Medical Center, Bedford, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Matson
authors.affiliation: Bedford VA Medical Center, Bedford, MA, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Bhasin
authors.affiliation: Department of Psychiatry and Behavioral Medicine, Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhu
authors.affiliation: RIKEN Center for Genomic Medicine, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: RIKEN Center for Genomic Medicine, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Behavioral Medicine, Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kaddurah-Daouk
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D000328:Adult; D002460:Cell Line; D015283:Citalopram / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012701:Serotonin / Q000097:blood; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D015283:Citalopram; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D059470:Tetraspanins; C556853:TSPAN5 protein, human