Convergent lines of evidence support <i>NOTCH4</i> as a schizophrenia risk gene.

Abstract

The association between <i>NOTCH4</i> and schizophrenia has been repeatedly reported. However, the results from different genetic studies are inconsistent, and the role of <i>NOTCH4</i> in schizophrenia pathogenesis remains unknown. Here, we provide convergent lines of evidence that support <i>NOTCH4</i> as a schizophrenia risk gene. We first performed a meta-analysis and found that a genetic variant (rs2071287) in <i>NOTCH4</i> 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 <i>NOTCH4</i> expression (p=1.08×10^-14) in human brain tissues, suggesting that rs2071287 may confer schizophrenia risk through regulating <i>NOTCH4</i> expression. <i>Sherlock</i> integrative analysis using a large-scale schizophrenia GWAS and eQTL data from human brain tissues further revealed that <i>NOTCH4</i> 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 <i>NOTCH4</i> expression. Consistently, we found that <i>NOTCH4</i> was significantly downregulated in brains of schizophrenia patients compared with controls (p=2.53×10^-3), further suggesting that dysregulation of <i>NOTCH4</i> may have a role in schizophrenia. Finally, we showed that <i>NOTCH4</i> regulates proliferation, self-renewal, differentiation and migration of neural stem cells, suggesting that <i>NOTCH4</i> may confer schizophrenia risk through affecting neurodevelopment. Our study provides convergent lines of evidence that support the involvement of <i>NOTCH4</i> in schizophrenia. In addition, our study also elucidates a possible mechanism for the role of <i>NOTCH4</i> in schizophrenia pathogenesis.