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Objective: To identify additional loci associated with depression and the hippocampus (HIP) through genome-wide association study., Methods: The depression-related genome-wide association study (GWAS) meta summary data was downloaded from the official website of the Psychiatric Genomics Consortium, which had involved 170 756 cases and 329 443 controls. The left and right hippocampal volume GWAS data sets were downloaded from the UK Biobank, which involved 33 224 participants. The conditional false discovery rate (condFDR) was used to identify novel genetic loci for depression and left and right hippocampal volumes, and a conjunctional false discovery rate (conjFDR) was used to evaluate the enrichment of pleiotropic loci between depression and left and right hippocampal volumes., Results: Respectively, 7, 13, and 12 new loci have been associated with depression, left hippocampal volume and right hippocampal volume, with a significant threshold of condFDR < 0.01. A site of rs1267073 locus was found to be shared by the depression and right hippocampal volume with a threshold of conjFDR < 0.01., Conclusion: Above findings have provided more insights into the genetic mechanisms underlying the volume of hippocampus and the risk for depression. The results may also provide evidence for future clinical trials for treating depression.

Background: Genome-wide association studies (GWASs) are used to identify genetic variants for association with bipolar disorder (BD) risk; however, each GWAS can only reveal a small fraction of this association. This study systematically analyzed multiple GWAS data sets to provide further insights into potential causal BD processes by integrating the results of Psychiatric Genomics Consortium Phase I (PGC-I) for BD with core human pathways and functional networks., Methods: The i-Gsea4GwasV2 program was used to analyze data from the PGC-I GWAS for BD (the pathways came from Reactome), as well as the nominally significant pathways. We established a gene network of the significant pathways and performed a gene set analysis for each gene cluster of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) GWAS data for the volumes of the intracranial region and seven subcortical regions., Results: A total of 30 of 1816 Reactome pathways were identified and showed associations with BD risk. We further revealed 22 interconnected functional and topologically interacting clusters (Clusters 0-21) that were associated with BD risk. Moreover, we obtained brain transcriptome data from BrainSpan and found significant associations between common variants of the genes in Cluster 1 with the hippocampus (HIP; P = .026; family-wise error [FWE] correction) and amygdala (AMY; P = .016; FEW correction) in Cluster 8 with HIP (P = .022; FWE correction). The genes in Cluster 1  were  enriched  for the transcriptional co-expression profile in the prenatal AMY, and core genes (CDH4, MTA2, RBBP4, and HDAC2) were identified to be involved in regulating early brain development., Conclusion: This study demonstrated that the HIP and AMY play a central role in neurodevelopment and BD risk., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previous research has demonstrated that the behaviors observed in chronic unpredictable mild stressed (CUMS) rats are similar to the symptoms of depressed patients and that the abnormal expression of cerebral microRNAs is associated with depressive disorder. However, little is known regarding the expression profile of microRNAs induced by CUMS. In this study, we aimed to examine the hippocampal microRNA expression profile in CUMS rats. Forty adolescent male Sprague-Dawley rats were randomly divided into normal and model groups. The rats in the model group were stimulated daily with randomly applied mild stressors from among 14 different mild stressors. The stressors were changed every day and were applied for 35 consecutive days. On the 28th and 35th days after treatment, the weights, physical condition, sucrose preference, and open-field test scores of the rats of the two groups were evaluated. Successful induction of CUMS was considered if the differences of the above metrics between the two groups were statistically significant on the 28th and 35th days after treatment. Cerebral sucrose metabolism images of rats were obtained by 18F-FDG PET/CT. The rats were euthanized under anesthesia, and hippocampal tissues were collected for hematoxylin-eosin (HE) staining. In addition, the samples were used for microRNA array chip and qRT-PCR analysis. The target genes of different microRNAs were predicted using bioinformatic analysis, and the functions and signal pathways of these target genes were investigated by GO and KEGG analyses. Sixteen rats exhibited successful induction of CUMS. Cerebral 18 F-FDG PET/CT imaging showed that the glucose metabolism rate of CUMS rats were significantly lower than normal rats in the central nucleus of the inferior colliculus (CIC, p = 0.022), the retrosplenial agranular area (RSA, p = 0.002), the second sensory cortex (S2, p = 0.028), the first auditory cortex (Au1, p = 0.012), the primary somatosensory cortex, barrel field (SIBF, p = 0.001), and the ventral posteromedial nucleus (VPM) of the right thalamus (p = 0.048). HE staining showed that hippocampal pyramidal cells CUMS rats were thinner, disordered, and exhibited irregular shapes, with many pyknotic cells. The microarray chip and qRT-PCR analysis revealed that five microRNAs were significantly up-regulated [miR-382-3p (p = 0.026), miR-183-5p (p = 0.018), miR-3573-5p (p = 0.042), miR-202-3p (p = 0.016), miR-493-3p (p = 0.009)], and only miR-370-3p was significantly down-regulated (p = 0.036). miRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with depression. Our findings provide supportive evidence for the abnormal expression of multiple CUMS-induced hippocampal microRNAs in rats as well as the involvement of these microRNAs in depressive disorder.

Depression is a major social and health concern, and ketamine exerts a quick, remarkable and persistent anti-depressive effect. microRNAs (miRNAs) show remarkable potential in the treatment of clinical depression. Here, we determined the expression profile of miRNAs in the hippocampus of rats treated with ketamine (15 mg/kg). The results suggest that multiple miRNAs were aberrantly expressed in rat hippocampus after ketamine injection (18 miRNAs were significantly reduced, while 22 miRNAs were significantly increased). Among them, miR-206 was down-regulated in ketamine-treated rats. In both cultured neuronal cells in vitro and hippocampus in vivo, we identified that the brain-derived neurotrophic factor (BDNF) was a direct target gene of miR-206. Via this target gene, miR-206 strongly modulated the expression of BDNF. Moreover, overexpression of miR-206 significantly attenuated ketamine-induced up-regulation of BDNF. The results indicated that miRNA-206 was involved in novel therapeutic targets for the anti-depressive effect of ketamine.

Background: Previous studies have inferred a strong genetic component for insomnia. However, the etiology of insomnia is still unclear. The aim of the current study was to explore potential biological pathways, gene networks, and brain regions associated with insomnia. Methods: Using pathways (gene sets) from Reactome, we carried out a two‐stage gene set enrichment analysis strategy. From a large genome‐wide association studies (GWASs) of insomnia symptoms (32,155 cases/26,973 controls), significant gene sets were tested for replication in other large GWASs of insomnia complaints (32,384 cases/80,622 controls). After the network analysis of unique genes within the replicated pathways, a gene set analysis for genes in each cluster/module of the enhancing neuroimaging genetics through meta‐analysis GWAS data was performed for the volumes of the intracranial and seven subcortical regions. Results: A total of 31 of 1,816 Reactome pathways were identified and showed associations with insomnia risk. In addition, seven functionally and topologically interconnected clusters (clusters 0–6) and six gene modules (named Yellow, Blue, Brown, Green, Red, and Turquoise) were associated with insomnia. Moreover, significant associations were detected between common variants of the genes in Cluster 2 with hippocampal volume (p = 0.035; family wise error [FWE] correction) and the red module with intracranial volume (p = 0.047; FWE correction). Functional enrichment for genes in the Cluster 2 and the Red module revealed the involvement of immune responses, nervous system development, NIK/NF‐kappaB signaling, and I‐kappaB kinase/NF‐kappaB signaling. Core genes (UBC, UBB, and UBA52) in the interconnected functional network were found to be involved in regulating brain development. Conclusions: The current study demonstrates that the immune system and the hippocampus may play central roles in neurodevelopment and insomnia risk. [ABSTRACT FROM AUTHOR]