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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]

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]