Rs7219 Regulates the Expression of GRB2 by Affecting MiR-1288-Mediated Inhibition and Contributes to the Risk of Schizophrenia in the Chinese Han Population

In the present study, we examined a potential genetic association between the variant rs7219 within the 3'-UTR of GRB2 and the susceptibility to schizophrenia (SCZ) and bipolar disorder (BD) in the Chinese Han population. A genetic association study, including 548 SCZ patients, 512 BD patients, and 598 normal controls, was conducted in the Chinese Han population. Genotyping was performed through the Sequenom MassARRAY technology platform. The expression of GRB2 was detected using quantitative real-time polymerase chain reaction (qRT-PCR). A dual-luciferase reporter assay was performed to determine whether miR-1288 could bind to the 3'-UTR region of GRB2 containing rs7219. We found that rs7219 was significantly associated with the susceptibility to SCZ under different genetic models, including additive [OR (95% CI) = 1.24 (1.02-1.49), P = 0.027], dominant [OR (95% CI) = 1.31 (1.04-1.66), P = 0.025], and allelic models[OR (95% CI) = 1.24 (1.03-1.49), P = 0.027]. However, no significant associations were found between rs7219 and the risk for BD (all P > 0.05). Moreover, we observed that the expression of GRB2 significantly decreased in SCZ patients compared with the controls (P = 0.004). The dual-luciferase reporter assay showed that the minor allele C of rs7219 significantly decreased the luciferase activity by binding miR-1288 (P < 0.001). In summary, we are the first to reveal that rs7219 is significantly associated with the susceptibility to SCZ in the Chinese Han population. Moreover, the minor allele C of rs7219 is identified as a risk allele for SCZ because it generates a binding site for miR-1288, thereby resulting in decreased expression of GRB2 and ultimately increasing the risk of SCZ.