No association of GRIK4 polymorphisms with schizophrenia in the Chinese Han population

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Schizophrenia is a polygenic and psychiatric mental disorder with high heritability and worldwide prevalence (Fromer et al., 2014). Genetic and cytogenetic evidence supports that the glutamate receptor gene, GRIK4, is associated with schizophrenia (Pickard et al., 2006). However, Shibata et al. (2006) concluded that single-nucleotide polymorphisms (SNPs) in GRIK4 gene did not play a major role in schizophrenia pathogenesis in the Japanese population. The largest genome-wide association study of schizophrenia has not reported any positive result on GRIK4 polymorphisms and schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Taking into account the controversial reports and the dearth of studies focusing on GRIK4 SNPs, we performed an association study to investigate whether SNPs in GRIK4 were associated with schizophrenia in the Chinese Han population.
A total of 1034 (409 women and 625 men, age: 45.06±12.88 years, age of onset: 25.98±9.65 years) unrelated schizophrenic patients, fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, and 1034 (446 women and 588 men, age: 34.06±10.00 years) healthy controls of Chinese Han origin were recruited for this study. The diagnostic of each patient was confirmed by a psychiatric examination performed by a board certified and experienced psychiatrist. The Ethics Committee of the Human Genetic Center of Shanghai approved this study and written informed consent was obtained from each patients. Genomic DNA was acquired from participants’ peripheral blood using the standard phenol–chloroform method. Hardy–Weinberg equilibrium tests and allelic and genotypic distribution studies between patients and healthy controls were performed using SHEsis software (Yong and Lin, 2005). R software package ‘genetics’ was adapted to estimate the association between SNPs and schizophrenia in five genetic models (codominant, dominant, recessive, overdominant and log-additive model).
Five SNPs (rs79526501, rs4582985, rs11218016, rs6589847, and rs56275759) of GRIK4 were genotyped by mass spectrometer using MassArray Analyzer 4 System (Sequenom iPLEXassay; San Diego, California, USA). The results showed that the observed genotypic distributions were all in Hardy–Weinberg equilibrium (P>0.05), except rs4582985 and rs56275759 (excluded from further analysis). The genotypes for the GRIK4 polymorphisms in cases and controls were distributed as follows: rs79526501: CC696: 16, CG302: 274, GG31: 35; rs11218016: CC455: 483, CT473: 436, TT101: 108; and rs6589847: AA32: 29, AG307: 314, GG690: 686. However, there was no significant difference in allelic or genotypic frequency distributions between patients and controls (P>0.05). Similarly, no positive results were found among these three SNPs and schizophrenia in any genetic models. Pairwise linkage disequilibrium estimates defined by r2 showed a strong linkage disequilibrium between rs11218016 and rs6589847 (D′=0.88, r2=0.356). Haplotype analysis was also performed using SHEsis (haplotype frequencies <3% were excluded from analysis). However, no significant association was found between this block and schizophrenia.
In conclusion, we did not find any significant association between GRIK4 polymorphisms and schizophrenia in the Chinese Han population. Taking into account the limitation of incomplete SNP coverage, studies on more SNP coverage and in larger samples are needed in the future.
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