Evidence of sex-modulated association of ZNF804A with schizophrenia

Genes, Cognition and Psychosis Program and Clinical, Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Biological psychiatry (Impact Factor: 9.47). 02/2011; 69(10):914-7. DOI: 10.1016/j.biopsych.2011.01.003
Source: PubMed

ABSTRACT The single nucleotide polymorphism (SNP) rs1344706 in ZNF804A (2q32.1) has been associated with schizophrenia in a genome-wide association study (GWAS). A recent candidate gene study, which replicated the positive association with rs1344706, identified another positive SNP (rs7597593) in ZNF804A associated with schizophrenia.
We performed an association study of rs7597593 in four GWAS cohorts of European ancestry. Postmortem human brain expression data of normal Caucasian individuals (n = 89) was also analyzed for examining the effect of rs7597593 on ZNF804A messenger RNA expression, using logistic regression and linear regression.
We found that rs7597593 was significantly associated with schizophrenia in the combined GWAS datasets (n = 5023, odds ratio [OR](combined) = 1.15, p = .0011). Analysis of stratification by sex showed that the association was driven by the female subjects (OR = 1.29, p = .0002) and was not significant in male subjects (OR = 1.08, p = .148) in the combined sample of four cohorts. A sex by genotype interaction was near significant in both the Genetic Association Information Network sample (p = .0532) and the combined sample of four cohorts (p(combined) = .0531). Gene expression analysis showed no main effects but a significant female-specific association (p(female) = .047, p(male) = .335) and sex by genotype interaction (p = .0166) for rs7597593.
Our data suggest a clinical and molecular modulation by sex of the association of ZNF804A SNP rs7597593 and risk of schizophrenia.

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    • "These findings suggest that ZNF804A abides by temporal patterns of expression regulation, in which the mechanism of rs1344706 cis-effects are pronounced in early fetal brain development. A putative risk SNP, rs7597593, has also been investigated to determine if it plays a role in mediating ZNF804A expression in the brain by examining the effects of genotype and sex on its mRNA expression in a sample of postmortem brains from Caucasian individuals [Zhang et al., 2011]. This study reports that rs7597593 cannot account for overall mRNA expression, yet when stratified for sex, rs7595793 appears to have an effect on ZNF804A expression that is female-specific. "
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    ABSTRACT: The gene that encodes zinc finger protein 804A (ZNF804A) became a candidate risk gene for schizophrenia (SZ) after surpassing genome-wide significance thresholds in replicated genome-wide association scans and meta-analyses. Much remains unknown about this reported gene expression regulator; however, preliminary work has yielded insights into functional and biological effects of ZNF804A by targeting its regulatory activities in vitro and by characterizing allele-specific interactions with its risk-conferring single nucleotide polymorphisms (SNPs). There is now strong epidemiologic evidence for a role of ZNF804A polymorphisms in both SZ and bipolar disorder (BD); however, functional links between implicated variants and susceptible biological states have not been solidified. Here we briefly review the genetic evidence implicating ZNF804A polymorphisms as genetic risk factors for both SZ and BD, and discuss the potential functional consequences of these variants on the regulation of ZNF804A and its downstream targets. Empirical work and predictive bioinformatic analyses of the alternate alleles of the two most strongly implicated ZNF804A polymorphisms suggest they might alter the affinity of the gene sequence for DNA- and/or RNA-binding proteins, which might in turn alter expression levels of the gene or particular ZNF804A isoforms. Future work should focus on clarifying the critical periods and cofactors regulating these genetic influences on ZNF804A expression, as well as the downstream biological consequences of an imbalance in the expression of ZNF804A and its various mRNA isoforms. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2014; 165(1). DOI:10.1002/ajmg.b.32207 · 3.27 Impact Factor
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    • "We have been able to confirm the association of rs7597593 as reported by Riley et al. (2010) and Zhang et al. (2011a). However, when stratifying for gender, it was revealed that mainly the male subgroup contributed to the results. "
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    ABSTRACT: Background Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a sample of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several samples with European- and Asian ancestral background.Methods We report ascertainment, clinical characterization, quality control, and determination of ancestral background of a case control sample from Indonesia, comprising 1067 cases and 1111 ancestry matched controls. Genotyping was performed using a fluorescence-based allelic discrimination assay (TaqMan SNP genotyping assay) and a newly designed PCR–RFLP assay for confirmation of rs1344706 genotypes.ResultsWe confirmed association of the T-allele of rs1344706 with schizophrenia in a newly ascertained sample from Indonesia with Southeast Asian ancestral background (P = 0.019, OR = 1.155, 95%, CI 1.025–1.301). In addition, we studied several SNPs in the vicinity of rs1344706, for which nominally significant results had been reported. None of the association P values of the additional SNPs exceeded that of rs1344706.Conclusion We provide additional evidence for association of the ZNF804A gene with schizophrenia. We conclude that rs1344706 or a yet unknown polymorphism in linkage disequilibrium is also involved in conferring susceptibility to schizophrenia in samples with different (Asian) ancestral backgrounds.
    Schizophrenia Research 06/2013; 147(1):46–52. DOI:10.1016/j.schres.2013.03.022 · 4.43 Impact Factor
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    • "gene (OMIM: 612282), which was statistically genome-wide significant for schizophrenia as well as bipolar disorders. Supporting evidence for this finding came from two recent meta-analyses (Williams et al., 2011; Zhang et al., 2011a) as well as three studies in which they have found rs7597593 and rs13423388 variants on chr2, even more profoundly associated with schizophrenia in a gender specific manner (Riley et al., 2010; Zhang et al., 2011a, 2011b; Sazci et al., 2012). Other GWASs have not replicated the evidence of association (Schanze et al., 2011). "
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    ABSTRACT: The ZNF804A rs1344706 variant was the first risk factor to be identified through genome-wide association studies and follow-up studies with meta-analysis for schizophrenia as well as bipolar disorders; we investigated 231 schizophrenia and 222 controls to see whether this particular variant was associated with schizophrenia in a Romanian population from Cluj Napoca. Clearly, there was no association between the ZNF804A rs1344706 variant and schizophrenia. Our study provides evidence for those that found no association with schizophrenia. A surprising result of our study was that the T allele frequency is the highest, thus far among the ethnic groups studied. We used a PCR-RFLP method that had been recently developed in our laboratory to the genotype ZNF804A rs1344706 variant. In conclusion, the ZNF804A rs1344706 variant was not associated with schizophrenia in the Romanian population from Cluj Napoca (χ(2)=0.734, p=0.693).
    Genetic Testing and Molecular Biomarkers 07/2012; 16(9):1135-7. DOI:10.1089/gtmb.2012.0066 · 1.15 Impact Factor
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Fengyu Zhang