Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample). Although the associations of both CREB1 SNPs with each illness were not replicated in the new cohorts (BPD analysis in 871 cases and 1089 controls (rs2709370, P=0.0611; rs6785, P=0.0544); SCZ analysis in 1273 cases and 1072 controls (rs2709370, P=0.230; rs6785, P=0.661); and MDD analysis in 129 cases and 100 controls (rs2709370, P=0.114; rs6785, P=0.188)), an overall meta-analysis of all included samples suggested that both SNPs were significantly associated with increased risk of BPD (11 105 cases and 51 331 controls; rs2709370, P=2.33 × 10^-4; rs6785, P=6.33 × 10^-5), SCZ (34 913 cases and 44 528 controls; rs2709370, P=3.96 × 10^-5; rs6785, P=2.44 × 10^-5) and MDD (9369 cases and 9619 controls; rs2709370, P=0.0144; rs6785, P=0.0314), with the same direction of allelic effects across diagnostic categories. We then examined the impact of diagnostic status on CREB1 mRNA expression using data obtained from independent brain tissue samples, and observed that the mRNA expression of CREB1 was significantly downregulated in psychiatric patients compared with healthy controls. The protein-protein interaction analyses showed that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS. In conclusion, the current study suggests that CREB1 might be a common risk gene for major psychiatric disorders, and further investigations are necessary.

中文翻译：

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cAMP反应元件结合（CREB）-1基因增加了发生严重精神疾病的风险。

躁郁症（BPD），精神分裂症（SCZ）和单相重度抑郁症（MDD）是原发性精神病，共有大量遗传危险因素。我们先前曾报道，cAMP反应元件结合（CREB）-1基因（CREB1）中的两个单核苷酸多态性（SNP）rs2709370和rs6785与欧洲血统人群中BPD风险和海马功能异常有关。在本研究中，我们进一步扩展了在多个BPD，SCZ和MDD数据集中对rs2709370和rs6785的分析，包括已发表的精神病基因组学协会（PGC）全基因组关联研究，我们先前的CREB1研究中使用的样本以及六个其他群组（三个新的BPD样本，两个新的SCZ样本和一个新的MDD样本）。^-4 ; rs6785，P = 6.33×10 ^-5），SCZ（34913个案例和44528个控件; rs2709370，P = 3.96×10 ^-5 ; rs6785，P = 2.44×10 ^-5）和MDD（9369例病例和9619例对照； rs2709370，P = 0.0144； rs6785，P = 0.0314），并且各个诊断类别的等位基因作用方向相同。然后，我们使用从独立的脑组织样本获得的数据检查了诊断状态对CREB1 mRNA表达的影响，并观察到与健康对照组相比，精神病患者中CREB1的mRNA表达显着下调。蛋白质-蛋白质相互作用分析表明，CREB1编码的蛋白质与GWAS鉴定的精神疾病的多个风险基因直接相互作用。总之，当前的研究表明CREB1可能是严重精神疾病的常见危险基因，因此有必要进行进一步的研究。