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Background and hypothesis Psychiatric disorders impose a huge health and economic burden on modern society. However, there is currently no proven completely effective treatment available, partly owing to the inefficiency of drug target identification and validation. We aim to identify therapeutic targets relevant to psychiatric disorders by conducting Mendelian randomization (MR) analysis. Study design We performed genome-wide MR analysis by integrating expression quantitative trait loci (eQTL) of 4479 actionable genes that encode druggable proteins and genetic summary statistics from genome-wide association studies of psychiatric disorders. After conducting colocalization analysis on the brain MR findings, we employed protein quantitative trait loci (pQTL) data as genetic proposed instruments for intersecting the colocalized genes to provide further genetic evidence. Study results By performing MR and colocalization analysis with eQTL genetic instruments, we obtained 31 promising drug targets for psychiatric disorders, including 21 significant genes for schizophrenia, 7 for bipolar disorder, 2 for depression, 1 for attention deficit and hyperactivity (ADHD) and none for autism spectrum disorder. Combining MR results using pQTL genetic instruments, we finally proposed 8 drug-targeting genes supported by the strongest MR evidence, including gene ACE, BTN3A3, HAPLN4, MAPK3 and NEK4 for schizophrenia, gene NEK4 and HAPLN4 for bipolar disorder, and gene TIE1 for ADHD. Conclusions Our findings with genetic support were more likely to be to succeed in clinical trials. In addition, our study prioritizes approved drug targets for the development of new therapies and provides critical drug reuse opportunities for psychiatric disorders. [ABSTRACT FROM AUTHOR]

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]

Recent genome-wide association studies have reported multiple schizophrenia risk loci, yet the functional variants and their roles in schizophrenia remain to be characterized. Here we identify a functional single nucleotide polymorphism (rs2270363: G>A) at the schizophrenia risk locus 16p13.3. rs2270363 lies in the E-box element of the promoter of NMRAL1 and disrupts binding of the basic helix-loop-helix leucine zipper family proteins, including USF1, MAX and MXI1. We validated the regulatory effects of rs2270363 using reporter gene assays and electrophoretic mobility shift assay. Besides, expression quantitative trait loci analysis showed that the risk allele (A) of rs2270363 was significantly associated with elevated NMRAL1 expression in the human brain. Transcription factors knockdown and CRISPR-Cas9-mediated editing further confirmed the regulatory effects of the genomic region containing rs2270363 on NMRAL1. Intriguingly, NMRAL1 was significantly downregulated in the brain of schizophrenia patients compared with healthy subjects, and knockdown of Nmral1 expression affected proliferation and differentiation of mouse neural stem cells, as well as genes and pathways associated with brain development and synaptic transmission. Of note, Nmral1 knockdown resulted in significant decrease of dendritic spine density, revealing the potential pathophysiological mechanisms of NMRAL1 in schizophrenia. Finally, we independently confirmed the association between rs2270363 and schizophrenia in the Chinese population and found that the risk allele of rs2270363 was the same in European and Chinese populations. These lines of evidence suggest that rs2270363 may confer schizophrenia risk by regulating NMRAL1, a gene whose expression dysregulation might be involved in the pathogenesis of schizophrenia by affecting neurodevelopment and synaptic plasticity. [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]