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Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population.

ABSTRACT: Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs) and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for schizophrenia in Han Chinese is inconclusive. Here, we conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population by combining all available case-control samples (N?=?12), including a total of 8,982 cases and 12,342 controls. The results of our meta-analysis were not able to confirm an association of rs1344706 A-allele with schizophrenia (p?=?0.10, odds ratio?=?1.06, 95% confidence interval?=?0.99-1.13). Such absence of association was further confirmed by the non-superiority test (p?=?0.0003), suggesting that rs1344706 is not a risk SNP for schizophrenia in Han Chinese. Detailed examinations of individual samples revealed potential sampling bias in previous replication studies in Han Chinese. The absence of rs1344706 association in Han Chinese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating genome-wide association findings of schizophrenia across different ethnic populations.

SUBMITTER: Li M

PROVIDER: S-EPMC3680487 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population.

Li Ming M Zhang Hui H Luo Xiong-jian XJ Gao Lei L Qi Xue-bin XB Gourraud Pierre-Antoine PA Su Bing B

PloS one 20130612 6

Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs) and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for ...[more]

PMID: 23776546

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Project description:Abstract Background: Following both meta-analysis and extensive resequencing, the single-nucleotide polymorphism of allele A, rs1344706, located in intron 2 of the zinc-finger protein gene ZNF804A, continues to be the common variant most strongly associated with schizophrenia risk (P = 1.1_10–13). ZNF804a is highly expressed in adult brain and functional effects on both protein expression, and altered DNA–protein interaction have been reported. In addition, the ZNF804A rs1344706 A allele has recently been reported to be associated with worse clinical outcome. We were interested in examining whether another proxy for worse clinical outcome, the Positive and Negative Syndrome Scale (PANSS) excitement factor, is associated with a ZNF804a genotype. We hypothesized that a single-nucleotide polymorphism in ZNF804a could be associated with impulsivity. The aim of this study was to assess the association of a single-nucleotide polymorphism rs1344706 with the PANSS excitement factor. Methods: We tested the effect of rs1344706 (A/C) genotype in 133 individuals with DSM-5 chronic schizophrenia using the PANSS. Scores on the PANSS excitement factor were compared between individuals who expressed allele A and those who expressed allele C (individuals with the heterogeneous allele A/C were combined to the C group). General Linear Model (GLM) was used to analyze the differences between groups for the PANSS Excitement Factor (assessed by the summation of: excitement, hostility, uncooperativeness, and poor impulse control). Results: A total of 133 subjects were sampled for ZNF804; however, PANSS data were available for 122 subjects. Of the 122, 68.85% (n = 84) of subjects presented with allele A and 31.15% (n = 38) with allele C. In all, 67.85% (n = 57) of the individuals with allele A were African Americans, and 28.95% (n = 11) of individuals with allele C were African Americans, and 39.47% (n = 15) were Hispanics. The PANSS total score for the entire sample was 72.64 (SD = 9.33). PANSS excitement factor scores ranged from 4 to 15 in group A and 4 to 14 in group C. GLM analysis showed a significant difference in ZNF804, F(1, 121) = 5.595, P = .020, between individuals with allele A compared to those with allele C. The mean excitement factor score for allele A was lower (mean = 7.762, SE = 0.273) than for allele C group (mean = 8.921, SE = 0.427). Conclusion: While the risk “A” allele at rs1344706 has been associated with altered functional brain connectivity and represents a risk factor for psychosis, our results shows an association of the “C” allele at rs1344706 with impulsivity in chronic schizophrenia patients. The difference in our findings when compared to previous reports may have to do with the differing ethnic distribution of our population, which is predominantly African American. This finding could be of nosological value for biological subtyping across the spectrum of schizophrenia, although important limitations should be noted such as small sample size and lack of ethnic diversity of our population.

Project description:The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706.To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder.Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder.Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype.ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P?=?.02). In contrast, full-length ZNF804A showed no association with genotype (P?>?.05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P?=?.006) and increased in those with major depressive disorder (P?<?.001), and there was a genotype-by-diagnosis interaction in bipolar disorder (P?=?.002). ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and nuclear staining. No differences in ZNF804A-immunoreactive neurons were seen in schizophrenia or related to rs1344706 (P?>?.05).rs1344706 influences the expression of ZNF804AE3E4, a novel splice variant. The effect is limited to fetal brain and to this isoform. It may be part of the mechanism by which allelic variation in ZNF804A affects risk of psychosis. ZNF804A is translated in human brain, where its functions may extend beyond its predicted role as a transcription factor.

Dataset Information

Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population.

Publications

Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population.

Similar Datasets

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