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: 10.26). 02/2011; 69(10):914-7. DOI: 10.1016/j.biopsych.2011.01.003
Source: PubMed


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 · 3.42 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 · 3.92 Impact Factor
    • "Association between rs1344706, recently acknowledged as a functional polymorphism,3 and the broader psychosis phenotype was confirmed in a nonoverlapping large multiethnic European sample,4 although not every dataset surveyed has shown positive association.5 A recent meta-analysis of rs1344706 in all available datasets provided strong evidence for association with schizophrenia (P = 2.54×10–11) and the extended psychosis phenotype, and there was no evidence for heterogeneity across studies.6 Association with ZNF804A variants has expanded to include potentially new candidates such as rs7597593 that was found to be preferentially associated with schizophrenia in the Irish Case–Control Study of Schizophrenia.7 In a recent study, Zhang et al8 reported that the association with rs7597593 in several large public GWAS datasets may show sex modulation, being especially strong in females. Overall, there is now substantial evidence for the involvement of ZNF804A in psychosis vulnerability. "
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    ABSTRACT: Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level.
    Schizophrenia Bulletin 11/2012; 39(6). DOI:10.1093/schbul/sbs110 · 8.45 Impact Factor
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