ERICH3: vesicular association and antidepressant treatment response

Duan Liu,Yani Wang,Daniel C Kim,Yongxian Zhuang,Huanyao Gao,Jia Yu,Lingxin Zhang,Liewei Wang,Tania Carrillo-Roa,Rima Kaddurah‐Daouk ,Thanh Thanh L Nguyen ,Elisabeth B Binder,Boadie W Dunlop,Erica Liu,Drew Neavin,Helen S Mayberg,W Edward Craighead,Joanna M Biernacka,Sisi Qin,Mark A Frye,Richard M Weinshilboum

doi:10.1038/s41380-020-00940-y

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) 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 ERICH3 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. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.

Highlights

Major depressive disorder (MDD) is the most common psychiatric disease and a major cause of medical disability worldwide [1, 2]
When we initially identified ERICH3 as a “top hit” in our original genome-wide association studies (GWAS), it was an uncharacterized gene that was most highly expressed in human brain [20,21,22]
That GWAS identified an single-nucleotide polymorphism (SNP) signal in ERICH3 that was associated with plasma serotonin concentrations which were themselves associated with selective serotonin reuptake inhibitors (SSRIs) response in MDD patients enrolled in the Mayo PGRN-AMPS SSRI trial [15]

Summary

Introduction

Major depressive disorder (MDD) is the most common psychiatric disease and a major cause of medical disability worldwide [1, 2]. Relative deficiency of the monoamine neurotransmitter serotonin (5-HT) appears to play a role in the pathophysiology of MDD and, as a result, drugs such as Several genome-wide association studies (GWAS) for SSRI treatment outcomes have been performed [5,6,7,8,9], but few of the top signals from those GWAS have been replicated or functionally validated [10, 11] This situation may result, in part, from MDD phenotypic heterogeneity and/or the lack of biologically based phenotypes [12]

Methods

Results

Conclusion