Replicated risk CACNA1C variants for major psychiatric disorders may serve as potential therapeutic targets for the shared depressive endophenotype.
Replicated risk CACNA1C variants for major psychiatric disorders may serve as potential therapeutic targets for the shared depressive endophenotype.
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发表时间：
2020
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通讯作者：
Luo X
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作者：
Guo X;Fu Y;Zhang Y;Wang T;Lu L;Luo X;Wang K;Huang J;Xie T;Zheng C;Yang K;Tong J;Zuo L;Kang L;Tan Y;Jiang K;Li CR;Luo X
全基因组关联研究 (GWAS) 报告了风险变异与主要精神疾病 (MPD) 之间的大量关联，包括精神分裂症 (SCZ)、双相情感障碍 (BPD)、重度抑郁症 (MDD) 等。我们回顾了所有已发表的 GWAS，并提取了风险 SNP 和 MPD 之间的全基因组显着性 (p<10−6) 和重复关联。我们发现了位于 6 个基因中的 6 个变异的关联，包括 L 型电压门控钙通道 (LTCC) 亚基 α1 C 基因 (CACNA1C)，这些变异在全基因组范围内显着 (2.0×10−8≤p≤1.0×10−6)，并且在至少两个 GWAS 中以单点水平复制。其中，MPD 与 CACNA1C 内的 rs1006737 之间的关联最为牢固。因此，下一步，分析了人类海马中复制的风险基因的表达。我们发现 CACNA1C 在两个独立队列的人类海马中具有显着的 mRNA 表达。最后，我们试图阐明文拉法辛和 ω−3 PUFA 在海马复制风险基因 mRNA 表达调控中的作用。我们使用基于 cDNA 芯片的微阵列分析来探索 ω−3 PUFA (0.72/kg/d) 和文拉法辛 (0.25/kg/d) 治疗对慢性轻度应激 (CMS) 大鼠的全转录组 mRNA 表达调节。 ω−3 PUFA 和文拉法辛治疗引起显着的 CACNA1C 上调。我们的结论是，CACNA1C 可能赋予 MPD 中共有的抑郁症状的遗传脆弱性，并且 CACNA1C 也可能是抑郁内表型的治疗靶点。
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 genome-wide 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 chip-based 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.