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Bipolar disorder (BIP) is one of the most common hereditary psychiatric disorders worldwide. Elucidating the genetic basis of BIP will play a pivotal role in mechanistic delineation. Genome-wide association studies (GWAS) have successfully reported multiple susceptibility loci conferring BIP risk, thus providing insight into the effects of its underlying pathobiology. However, difficulties remain in the extrication of important and biologically relevant data from genetic discoveries related to psychiatric disorders such as BIP. There is an urgent need for an integrated and comprehensive online database with unified access to genetic and multi-omics data for in-depth data mining. Here, we developed the dbBIP, a database for BIP genetic research based on published data. The dbBIP consists of several modules, i.e.: (i) single nucleotide polymorphism (SNP) module, containing large-scale GWAS genetic summary statistics and functional annotation information relevant to risk variants; (ii) gene module, containing BIP-related candidate risk genes from various sources and (iii) analysis module, providing a simple and user-friendly interface to analyze one's own data. We also conducted extensive analyses, including functional SNP annotation, integration (including summary-data-based Mendelian randomization and transcriptome-wide association studies), co-expression, gene expression, tissue expression, protein–protein interaction and brain expression quantitative trait loci analyses, thus shedding light on the genetic causes of BIP. Finally, we developed a graphical browser with powerful search tools to facilitate data navigation and access. The dbBIP provides a comprehensive resource for BIP genetic research as well as an integrated analysis platform for researchers and can be accessed online at http://dbbip.xialab.info. Database URL:   http://dbbip.xialab.info [ABSTRACT FROM AUTHOR]

p53-binding protein-1 (53BP1) plays a critical role in cell cycle checkpoint and DNA repair activities. Recently, 53BP1 was recognized as a potential tumor suppressor gene. In this study, we investigated its tumor suppressor function in breast cancer. In clinical samples, we observed a lower level of 53BP1 expression in the cancer lesions than in the matched non-tumor tissues. Furthermore, the 53BP1 level showed a gradual decrease during the progression from precancerous to cancer lesion. Ectopic expression of 53BP1 can significantly inhibit cell proliferation and curb the invasiveness in breast cancer cell lines, whereas knockdown of 53BP1 by RNA interference had the opposite effects. Additionally, 53BP1 markedly inhibited xenograft formation and metastasis of breast cancer cells in nude mice. Both in vitro and in vivo studies revealed that the 53BP1 expression level was inversely correlated to the function of nuclear factor-kappaB (NF-κB), which contributes to the invasion and metastasis of breast cancer. Importantly, the inhibitory effect of 53BP1 on NF-κB activity was shown to be mediated by the upregulation of miR-146a. Together, our findings demonstrated that 53BP1 has a potent tumor suppressor activity in breast cancer, and it may serve as a novel target for breast cancer prevention and treatment. [ABSTRACT FROM PUBLISHER]

Genome-wide association studies have identified 10q24.32 as a robust schizophrenia risk locus. Here we identify a regulatory variant (rs10786700) that disrupts binding of transcription factors at 10q24.32. We independently confirmed the association between rs10786700 and schizophrenia in a large Chinese cohort (n = 11 547) and uncovered the biological mechanism underlying this association. We found that rs10786700 resides in a super-enhancer element that exhibits dynamic activity change during the development process and that the risk allele (C) of rs10786700 conferred significant lower enhancer activity through enhancing binding affinity to repressor element-1 silencing transcription factor (REST). CRISPR-Cas9-mediated genome editing identified SUFU as a potential target gene by which rs10786700 might exert its risk effect on schizophrenia, as deletion of rs10786700 downregulated SUFU expression. We further investigated the role of Sufu in neurodevelopment and found that Sufu knockdown inhibited proliferation of neural stem cells and neurogenesis, affected molecular pathways (including neurodevelopment-related pathways, PI3K-Akt and ECM-receptor interaction signalling pathways) associated with schizophrenia and altered the density of dendritic spines. These results reveal that the functional risk single nucleotide polymorphism rs10786700 at 10q24.32 interacts with REST synergistically to regulate expression of SUFU , a novel schizophrenia risk gene which is involved in schizophrenia pathogenesis by affecting neurodevelopment and spine morphogenesis. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have shown that genetic variants at 2q33.1 are strongly associated with schizophrenia. However, potential causal variants in this locus and their roles in schizophrenia remain unknown. Here, we identified two functional variants (rs796364 and rs281759) that disrupt CTCF, RAD21 and FOXP2 binding at 2q33.1. We systematically investigated the regulatory mechanisms of these two variants with serial experiments, including reporter gene assays and electrophoretic mobility shift assay. Intriguingly, these two single nucleotide polymorphisms physically interacted with TYW5 and showed the most significant associations with TYW5 expression in human brain. Consistently, CRISPR-Cas9-mediated genome editing confirmed the regulatory effect of the two single nucleotide polymorphisms on TYW5 expression. Additionally, expression analysis indicated that TYW5 was significantly upregulated in brains of schizophrenia cases compared with controls, suggesting that rs796364 and rs281759 might confer schizophrenia risk by modulating TYW5 expression. We over-expressed TYW5 in mouse neural stem cells and rat primary neurons to mimic its upregulation in schizophrenia and found significant alterations in the proliferation and differentiation of neural stem cells, as well as dendritic spine density following TYW5 overexpression, indicating its important roles in neurodevelopment and spine morphogenesis. Furthermore, we independently confirmed the association between rs796364 and schizophrenia in a Chinese cohort of 8202 subjects. Finally, transcriptome analysis revealed that TYW5 affected schizophrenia-associated pathways. These lines of evidence consistently revealed that rs796364 and rs281759 might contribute to schizophrenia risk by regulating the expression of TYW5 , a gene whose expression dysregulation affects two important schizophrenia pathophysiological processes (i.e. neurodevelopment and dendritic spine formation). [ABSTRACT FROM AUTHOR]

The application of third-generation sequencing (TGS) technology in genetics and genomics have provided opportunities to categorize and explore the individual genomic landscapes and mutations relevant for diagnosis and therapy using whole genome sequencing and de novo genome assembly. In general, the emerging TGS technology can produce high quality long reads for the determination of overlapping reads and transcript isoforms. However, this technology still faces challenges such as the accuracy for the identification of nucleotide bases and high error rates. Here, we surveyed 39 TGS-related tools for de novo assembly and genome analysis to identify the differences among their characteristics, such as the required input, the interaction with the user, sequencing platforms, type of reads, error models, the possibility of introducing coverage bias, the simulation of genomic variants and outputs provided. The decision trees are summarized to help researchers to find out the most suitable tools to analyze the TGS data. Our comprehensive survey and evaluation of computational features of existing methods for TGS may provide a valuable guideline for researchers. [ABSTRACT FROM AUTHOR]