Abstract
Chromosome 6p21-p22.1, spanning the extended major histocompatibility complex (MHC) region, is a highly polymorphic, gene-dense region. It has been identified as a susceptibility locus of schizophrenia in Europeans, Japanese, and Chinese. In our previous two-stage genome-wide association study (GWAS), polymorphisms of zinc finger with KRAB and SCAN domains 4 (ZKSCAN4), nuclear factor-κB-activating protein-like (NKAPL), and piggyBac transposable element derived 1 (PGBD1), localized to chromosome 6p21-p22.1, were strongly associated with schizophrenia. To further investigate the association between polymorphisms at this locus and schizophrenia in the Chinese Han population, we selected eight other single-nucleotide polymorphisms (SNPs) distributed in or near these genes for a case-control association study in an independent sample of 902 cases and 1,091 healthy controls in an attempt to replicate the GWAS results. Four of these eight SNPs (rs12214383, rs1150724, rs3800324, and rs1997660) displayed a nominal difference in allele frequencies between the case and control groups. The association between two of these SNPs and schizophrenia were significant even after Bonferroni correction (rs12000: allele A>G, P = 2.50E-04, odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.12–1.45; rs1150722: allele C>T, P = 4.28E-05, OR = 0.55, 95% CI = 0.41–0.73). Haplotype ATTGACGC, comprising these eight SNPs (rs2235359, rs2185955, rs12214383, rs12000, rs1150724, rs1150722, rs3800324, and rs1997660), was significantly associated with schizophrenia (P = 6.60E-05). We also performed a combined study of this replication sample and the first-stage GWAS sample. The combined study revealed that rs12000 and rs1150722 were still strongly associated with schizophrenia (rs12000: allele G>A, P combined = 0.0019, OR = 0.81; rs1150722: allele G>A, P combined = 3.00E-04, OR = 0.61). These results support our findings that locus 6p21-p22.1 is significantly associated with schizophrenia in the Chinese Han population and encourage further studies of the functions of these genetic factors.
Highlights
Schizophrenia is a psychiatric disorder with a worldwide prevalence of up to 1% and highly heritable factors
Significant differences remained for rs12000 and rs1150722 after the corrections
The extended major histocompatibility complex (MHC) region has been implicated as a main factor in schizophrenia pathogenesis, supported by genome-wide association study (GWAS) of schizophrenia in different populations [18,19,20,21,22]
Summary
Schizophrenia is a psychiatric disorder with a worldwide prevalence of up to 1% and highly heritable factors. It is characterized by disturbances in thinking, emotion, cognition, and social function, including hallucinations, delusions, and apathy. Some studies have found negative results [8,9,10,11,12,13], this locus, especially the MHC region, is still a high susceptibility factor in schizophrenia [14]. Compared with classic MHC molecules, the histone supercluster, the Zinc-finger supercluster, the heat shock cluster, and other immune-related/unrelated genes have been found in the extended MHC region [15]
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