Brief Association Letters
Fyn, a nonreceptor tyrosine kinase, is abundantly expressed in the hippocampus, cerebral cortex, and thalamus (Ishiguro et al., 2000). By phosphorylating the N-methyl-D-aspartate (NMDA) NR2B subunit, Fyn regulates the glutamatergic signaling, which is implicated in the pathogenesis of schizophrenia. Here, we examined whether FYN polymorphisms (rs6916861, rs3730353, and rs706895) are risk factors for schizophrenia in the Chinese-Han population.
All experiments were carried out according to the methods described in our previous studies (Li et al., 2011). The schizophrenic group consisted of 384 individuals (range: 18–64 years). The diagnoses, according to the Diagnostic and Statistical Manual for Mental Disorders 4th ed. criteria, were performed independently by two senior psychiatrists. The healthy controls consisted of 502 individuals (range: 19–58 years) with no psychiatric diseases. All the protocols were approved by the Ethics Committee of China Medical University.
In both the schizophrenic and control groups, genotype distributions of FYN polymorphisms were all in Hardy–Weinberg equilibrium. The genotype frequencies of case/control were distributed as follows: rs706895 (CC=19.8%/18.3%; CT=46.9%/52.2%; TT=33.3%/29.5%), rs3730353 (TT=49.7%/52.2%; TC=40.9%/41.4%; CC=9.4%/6.4%), rs6916861 (AA=49.5%/50.6%; AC=41.1%/41.6%; CC=9.4%/7.8%). The ages at onset (years, mean±SD) of schizophrenia were as follows: rs706895 (CC=27.07±9.06; CT=27.49±8.13; TT=27.96±8.13), rs3730353 (TT=29.16±10.80; TC=27.30±7.64; CC=27.44±8.32), rs6916861 (AA=27.49±7.99; AC=27.29±8.05; CC=29.00±10.88). There were no differences in genotype or allele frequencies between the schizophrenic patients and controls (P>0.05, the χ2-test). No association between FYN polymorphisms and age at onset of schizophrenia was observed either (P>0.05, one-factor analysis of variance). Haplotype analysis revealed that rs6916861 and rs3730353 polymorphisms were in linkage disequilibrium (D=0.86, r2=0.71). The frequencies of the AT haplotype between the patients and controls were significantly different even after adjusting the significance level for multiple tests (P=0.001, corrected significance level=0.003).
The present study was designed on the basis of the NMDA receptor hypofunction hypothesis and the known ability of Fyn to regulate NMDA receptors through NR2B subunit phosphorylation. It has been suggested that increased expression of Fyn in the prefrontal cortex may contribute to the pathogenesis of schizophrenia (Ohnuma et al., 2003a). Moreover, Rybakowski et al. (2007) demonstrated that FYN polymorphisms (rs6916861 and rs3730353) were associated with performance on the Wisconsin Card Sorting Test of prefrontal executive function in schizophrenics. In this light, it is not surprising that the AT combination of the two FYN polymorphisms (rs6916861 and rs3730353) is associated with schizophrenia in our sample. In the single marker analysis, however, we found no association between FYN polymorphisms and schizophrenia risk or age at schizophrenia onset, which is consistent with previous studies in Japanese populations (Ishiguro et al., 2000; Ohnuma et al., 2003b). Therefore, these results should be confirmed in other ethnic groups. Further studies are required to analyze other allelic variants of FYN. In conclusion, our study provided suggestive evidence that FYN is a susceptible gene for schizophrenia in the Chinese-Han population.
This study was supported by a Grant from the project of Liaoning SHIBAIQIAN high-end talent and a Grant (2011408004) from Liaoning Science and Technology project for Prof. Gang Zhu.
Conflicts of interest
There are no conflicts of interest.
Ishiguro H, Saito T, Shibuya H, Toru M, Arinami T. Mutation and association analysis of the Fyn kinase gene with alcoholism and schizophrenia. Am J Med Genet. 2000;96:716–720
Li J, Ma H, Deng S, Wu L, Huang Y, Zhu G. Fyn polymorphisms are associated with distinct personality traits in healthy Chinese-Han subjects. J Mol Neurosci. 2011;44:1–5
Ohnuma T, Kato H, Arai H, McKenna PJ, Emson PC. Expression of Fyn, a non-receptor tyrosine kinase in prefrontal cortex from patients with schizophrenia and its correlation with clinical onset. Brain Res Mol Brain Res. 2003a;112:90–94
Ohnuma T, Shibata N, Matsubara Y, Sato S, Yamashina M, Arai H. No genetic association between polymorphisms in the Fyn kinase gene and age of schizophrenic onset. Neurosci Lett. 2003b;343:70–72
Rybakowski JK, Borkowska A, Skibinska M, Hauser J. Polymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia. Psychiatr Genet. 2007;17:201–204