The association between NOTCH4 and schizophrenia has been repeatedly reported. However, the results from different genetic studies are inconsistent, and the role of NOTCH4 in schizophrenia pathogenesis remains unknown. Here, we provide convergent lines of evidence that support NOTCH4 as a schizophrenia risk gene. We first performed a meta-analysis and found that a genetic variant (rs2071287) in NOTCH4 was significantly associated with schizophrenia (a total of 125 848 subjects, p=8.31×10−17), with the same risk allele across all tested samples. Expression quantitative trait loci (eQTL) analysis showed that rs2071287 was significantly associated with NOTCH4 expression (p=1.08×10−14) in human brain tissues, suggesting that rs2071287 may confer schizophrenia risk through regulating NOTCH4 expression. Sherlock integrative analysis using a large-scale schizophrenia GWAS and eQTL data from human brain tissues further revealed that NOTCH4 was significantly associated with schizophrenia (p=4.03×10−7 in CMC dataset and p=3.06×10−6 in xQTL dataset), implying that genetic variants confer schizophrenia risk through modulating NOTCH4 expression. Consistently, we found that NOTCH4 was significantly downregulated in brains of schizophrenia patients compared with controls (p=2.53×10−3), further suggesting that dysregulation of NOTCH4 may have a role in schizophrenia. Finally, we showed that NOTCH4 regulates proliferation, self-renewal, differentiation and migration of neural stem cells, suggesting that NOTCH4 may confer schizophrenia risk through affecting neurodevelopment. Our study provides convergent lines of evidence that support the involvement of NOTCH4 in schizophrenia. In addition, our study also elucidates a possible mechanism for the role of NOTCH4 in schizophrenia pathogenesis.
- psychotic disorders (incl schizophrenia)
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YZ, SL and XL contributed equally.
LL and XL contributed equally.
Contributors XJL conceived and designed the study. YZ and SWL performed the cellular and molecular experiments, including isolation of mouse NSCs, proliferation assays, migration and differentiation experiments, and qPCR. XYL performed the meta-analysis, Sherlock and SMR integrative analysis, cell-type specific expression analysis and spatio-temporal expression pattern analysis. YFY, WQL, XX, ML and LXL assisted in meta-analysis and molecular experiments. XJL supervised the study and wrote the manuscript. All authors critically read, revised and approved the final manuscript.
Funding This study was equally supported by the National Nature Science Foundation of China (31722029 and 31970561 to XJL) and the National Key Research and Development Program of China (Stem Cell and Translational Research) (2016YFA0100900). The study was also supported by the Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004), the Key Research Project of Yunnan Province (2017FA008 to XJL), the National Natural Science Foundation of China (81671330 and 81971252 to LXL, U1904130 to WQL), the Medical Science and Technology Research Project of Henan Province (LHGJ20190479 to YZ), the High Scientiﬁc and Technological Research Fund of Xinxiang Medical University (2017ZDCG-04 to LXL), the Open Program of Henan Key Laboratory of Biological Psychiatry (ZDSYS2016006 to YZ), and the support project for the Disciplinary group of Psychiatry and Neuroscience, Xinxiang Medical University. One of the brain eQTL datasets used in this study was generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: Pamela Sklar, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici, Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite, Mette Peters (Sage Bionetworks), Thomas Lehner and Barbara Lipska (NIMH). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information. The data generated in this study will be available from the corresponding author on reasonable request.
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