Association between insertion/deletion polymorphism in intron 3 of XRCC4 and susceptibility to type I bipolar disorder.

Abstract

The ubiquitously expressed X-ray repair cross-complementation group 4 (XRCC4; OMIM: 194363) is an essential repair protein involved in the nonhomologous end-joining (NHEJ) pathway for DNA double-strand breaks (DSBs) repair. The NHEJ is the major pathway that repairs DNA DSBs in mammalian species (Li et al., 1995). Several genetic variations in the gene encoding XRCC4 have been reported, including a 30 bp sequence insertion/deletion in intron 3 of the gene (rs28360071, Ins/Del). Previously, it has been reported that the polymorphisms of XRCC1 were associated with a risk of type I bipolar disorder (BPI) (Saadat et al., 2012). However, the association between DNA repair capacity and susceptibility to BPI has been reported (Benes, 2010). On the basis of results of the previous studies, it is suggested that the rs28360071 polymorphism may alter the normal expression and/or the protein function of XRCC4. Taken together, it could be suggested that the polymorphism of XRCC4 may be associated with a risk of BPI. To our knowledge, no results have been reported on the relationship between the Ins/Del polymorphism of XRCC4 and susceptibility to BPI; therefore, the present case–control study was carried out. A detailed description of the study participants has been reported in our previous report (Mohammadynejad et al., 2011). The diagnoses were made by the clinician according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnostic criteria. Inclusion criteria for patients were age 16–65 years with type I BPI. We lost DNA of seven control participants; therefore, the present case–control study included 228 (169 males, 59 females) patients with BPI and 229 (176 males, 53 females) healthy blood donors frequency matched to the patients by age and sex (P>0.05). The genotypes were determined using a PCR method as described previously (Chang et al., 2008). The frequency of Ins/Ins, Ins/Del, and Del/Del genotypes was 63, 122, and 43 among the cases and 72, 116, and 41 among the controls, respectively. The genotypic frequency for the rs28360071 polymorphism among the controls was in Hardy–Weinberg equilibrium (P>0.05). The association between the XRCC4 Ins/Del polymorphism and the risk of BPI was not significant either in Ins/Del (odds ratio=1.20, 95% confidence interval=0.79–1.83, P=0.394) or in Del/Del (odds ratio=1.20, 95% confidence interval=0.69–2.07, P=0.515) genotypes compared with the Ins/Ins genotype. Both dominant and recessive models showed no association between the single-nucleotide polymorphism genotypes and the risk of BPI (P>0.05). The XRCC4 protein plays an important role in the NHEJ pathway for DNA DSBs repair (Li et al., 1995). The XRCC4 is expressed in the brain (Li et al., 1995). Also, the association between cellular DNA repair capacity and susceptibility to BPI has been suggested (Benes, 2010); therefore, we hypothesized that the Ins/Del polymorphism of XRCC4 might be associated with susceptibility to BPI. However, the present finding did not support our hypothesis. The present study has some limitations. First, several polymorphisms have been identified in XRCC4, whereas we studied only one polymorphism. Second, although the control participants had no diagnosis of BPI or other psychotic disorders, they may have had a positive family history of psychotic disorder. Third, the small sample size is another limitation. It is therefore important to gather data from several large studies before final conclusions on the involvement of the Ins/Del XRCC4 polymorphism in type I BPI can be drawn. Acknowledgements The authors are indebted to the participants for their cooperation. This study was supported by Shiraz University. Conflicts of interest There are no conflicts of interest.