Association study of the GLRX5 rs1007814 polymorphism with schizophrenia in the Han Chinese population

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Schizophrenia is a highly heritable and devastating psychiatric disorder, which is characterized by delusions, hallucinations, emotional deterioration, and other unusual behaviors. However, the precise etiology and mechanism of schizophrenia is still unclear. A recent review showed that genetic and physiological components of mitochondria have been implicated in the etiology of schizophrenia (Rajasekaran et al., 2015). Consistent with the critical function of mitochondria, genetic mutations in a number of Fe–S cluster genes lead to severe neurological diseases, often beginning as early as childhood (Stehling et al., 2014). GLRX5 is highly conserved evolutionarily and is associated with an Fe–S cluster biosynthetic defect within the mitochondria. Here, for the first time, we investigate whether the GLRX5 rs1007814 confers the risk of schizophrenia in the Han Chinese population.
In this case–control study, all patients who provided written informed consent were of Han Chinese origin: 611 (278 women and 333 men; age: 42.0±9.9 years) healthy controls and 893 (389 women and 504 men; age: 50.4±13.4 years) schizophrenic patients. Clinical interviews were performed by at least two board-certified psychiatrists and were diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., criteria. The study was reviewed and approved by the Shanghai Ethical Committee of Human Genetic Resources. Genomic DNA was extracted from peripheral blood samples obtained from each participant using the standard phenol–chloroform method. All statistical analyses were carried out using a powerful online software SHEsis (http://analysis.bio-x.cn/myAnalysis.php). No significant deviation from Hardy–Weinberg equilibrium was found in the controls for rs1007814 polymorphisms (P=0.14).
GLRX5 rs1007814 showed a statistically marginally significant difference between cases and controls in genotype frequency (case/control: CC 1:6; CT 112:78; TT 752:505, P=0.049361), but no significant differences in allele distribution [odds ratio (OR)=0.852805, 95% confidence interval (CI)=0.640128–1.136144, P=0.276211]. Furthermore, a further stratified analysis on the basis of sex was also carried out. In men, we found a minor difference in the genotype frequency (case/control: CC 0:3; CT 72:36; TT 411:280, P=0.037370) and not in allele distribution (OR=1.142857, 95% CI=0.770369–1.695451, P=0.506742). In women, we failed to find an association of the rs1007814 genotype frequency with susceptibility to schizophrenia (case/control, CC 1:3, CT 40:42, TT 341:225, P=0.056328), rather than allele distribution (OR=0.596260, 95% CI=0.387995–0.916317, P=0.017343).
To our knowledge, this is the first study of an association between GLRX5 rs1007814 and schizophrenia. Mitochondria play a critical role in neurodevelopment and neuronal functions (Clay et al., 2011). GLRX5 deficiency causes a generalized assembly defect of mitochondrial Fe–S cluster (Ye and Rouault, 2010). Most studies have focused on the association between mtDNA haplogroups, mitochondrial single nucleotide polymorphisms (SNPs), and schizophrenia. In different Chinese populations, mtDNA haplogroup N9a conferred susceptibility to schizophrenia, whereas haplogroup B5a was identified to be a potential factor for schizophrenia. In contrast, a study has shown that mitochondrial SNPs in common European haplogroups do not confer a risk of schizophrenia (Rajasekaran et al., 2015). Therefore, the association between mtDNA SNPs and schizophrenia remains controversial and needs to be further validated. In studies of psychiatric patients, expressions of Fe–S cluster genes were significantly decreased in the prefrontal cortex in schizophrenia (Karry et al., 2004). Here, our results suggested a positive association study of GLRX5 rs1007814 with the risk of schizophrenia, which was a potential factor involved in mitochondrial function in the etiology of schizophrenia. To further elucidate whether GLRX5 variants are related to schizophrenia, a comprehensive analysis with more saturated SNPs coverage is necessary.
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