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Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (<jats:italic>ERICH3<\/jats:italic>) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human <jats:italic>ERICH3<\/jats:italic> gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. 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RK-D is inventor on key patents in the field of metabolomics in the study of CNS diseases and holds equity in Metabolon, Inc., a biotechnology company that provides metabolic profiling capabilities. BWD has received research support from Acadia, Axsome, Intra-Cellular Therapies, Janssen, and Takeda; he has served as a consultant to Myriad Neuroscience and Aptinyx. HSM has received consulting and IP licensing fees from Abbott Labs. MAF has received research support from Assurex Health, Myriad, Mayo Foundation, and Medibio; he has served as a consultant for Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem Inc., Sanofi, Takeda, Teva Pharmaceuticals; he has received CME Travel\/Honoraria from American Physician Institute, CME Outfitters, Global Academy for Medical Education. All other authors declared no competing interests for this work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}