Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene

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.