J Neurosci Cogn Stud | Volume 4, Issue 1 | Research Article | Open Access

Replicated Risk CACNA1C Variants for Major Psychiatric Disorders May Serve as Potential Therapeutic Targets for the Shared Depressive Endophenotype

Xiaoyun Guo^1,2,3*, Yingmei Fu^1,4, Yong Zhang⁵, Tong Wang³, Lu Lu⁶, Xingqun Luo⁷, Kesheng Wang⁸, Juncao Huang⁹, Ting Xie⁹, Chengchou Zheng¹⁰, Kebing Yang⁹, Jinghui Tong⁹, Lingjun Zuo², Longli Kang¹¹, Yunlong Tan⁹, Kaida Jiang^1*, Chiang-shan R. Li² and Xingguang Luo^2,9

¹Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, China
²Department of Psychiatry, Yale University School of Medicine, USA
³Department of Cellular and Molecular Physiology, Yale University School of Medicine, USA
⁴Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University School of Medicine, China
⁵Tianjin Mental Health Center, China
⁶Departments of Genetics, Genomics, Informatics, Anatomy and Neurobiology, University of Tennessee Health
Science Center, USA
⁷Department of Clinical Medicine, College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, China
⁸Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, USA
⁹Biological Psychiatry Research Center, Beijing Huilongguan Hospital, China
¹⁰Minqing Psychiatric Hospital, Minqing, China
¹¹Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xiangyang, China

^*Correspondance to: Xiaoyun Guo 

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Abstract

Genome-Wide Association Studies (GWASs) have reported numerous associations between risk variants and Major Psychiatric Disorders (MPDs) including Schizophrenia (SCZ), Bipolar Disorder (BPD), Major Depressive Disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p<10-6) and replicated associations between risk SNPs and MPDs. We found the associations of 6 variants located in 6 genes, including L Type Voltage-Gated Calcium Channel (LTCCs) subunit alpha1 C gene (CACNA1C), that were genomewide significant (2.0 × 10-8 ≤ p ≤ 1.0 × 10-6) and replicated at single-point level across at least two GWASs. Among them, the associations between MPDs and rs1006737 within CACNA1C are most robust. Thus, as a next step, the expression of the replicated risk genes in human hippocampus was
analyzed. We found CACNA1C had significant mRNA expression in human hippocampus in two independent cohorts. Finally, we tried to elucidate the roles of venlafaxine and ω-3 PUFAs in the mRNA expression regulation of the replicated risk genes in hippocampus. We used cDNA chipbased microarray profiling to explore the transcriptome-wide mRNA expression regulation by ω-3 PUFAs (0.72/kg/d) and venlafaxine (0.25/kg/d) treatment in Chronic Mild Stress (CMS) rats. ω-3 PUFAs and venlafaxine treatment elicited significant CACNA1C up-regulation. We concluded that CACNA1C might confer the genetic vulnerability to the shared depressive symptoms across MPDs and CACNA1C might be the therapeutic target for depressive endophenotype as well.

Keywords:

CACNA1C; Major Psychiatric Disorders (MPD); Schizophrenia (SCZ); Bipolar Disorder (BPD); Major Depressive Disorder (MDD); Genome-Wide Association Study (GWAS)

Citation:

Guo X, Fu Y, Wang T, Zhang Y, Lu L, Wang K, et al. Replicated Risk CACNA1C Variants for Major Psychiatric Disorders May Serve as Potential Therapeutic Targets for the Shared Depressive Endophenotype. J Neurosci Cogn Stud. 2020; 4(1):1017..