Clinical symptomatology and the psychosis risk gene ZNF804A

Abstract

Clinical symptomatology and the psychosis risk gene ZNF804A Dear Editors,The single nucleotide polymorphism (SNP) rs1344706, mapping to the gene ZNF804A, has been implicated in schizophrenia susceptibility (O'Donovan et al. 2008; International Schizophrenia Consortium, 2009;Stefansson et al. 2009;Steinberg et al. 2010). The original study reported stronger association when the phenotype was broadened to include bipolar disorder (p = 9.96 × 10 − 9 ) (O'Donovan et al. 2008), but the variant is likely to have a modest effect on disease risk (OR = 1.12). Understanding the function of psychosis risk genes is a key step towards understanding disease biology. Little is currently known about the encoding protein, zinc finger protein 804A, except that it is brainexpressed and predicted to be involved in regulation of gene expression. Two recent studies suggest that the ZNF804A risk allele is likely to influence brain function, both with respect to connectivity within and between the dorsolateral prefrontal cortex and hippocampus (Esslinger et al. 2009) and on episodic and working memory (Walters et al. in press).An unanswered question is whether this gene has an effect at the level of clinical symptomatology within patient populations. Specifically, does this risk variant delineate a specific form of illness on the mood-psychosis spectrum (Craddock et al. 2006). For this study we investigated clinical symptom factors in a large sample (n = 820) of Irish psychotic patients. The study included 820 patients with a DSM-IV diagnosis of schizophrenia (N = 568), schizoaffective disorder (N = 127) or bipolar affective disorder (N = 125). Because clinical symptoms can vary over time we analyzed two measures of clinical symptomatology based on lifetime severity (BADDS) and presence of specific symptoms (Operational Criteria Checklist for Psychotic Illness, OPCRIT) (McGuffin et al. 1991).SNP rs1344706 was genotyped using a Taqman ® SNP Genotyping Assay on a 7900HT Sequence Detection System (Applied Biosystems) (n = 529) and the Sequenom iPLEX Gold system (n = 291) (detailed in Walters et al. in press). The call rate for both genotyping platforms was N95%. Both case/control samples were in Hardy-Weinberg Equilibrium (HWE; p N 0.05). A number of HapMap CEU DNA samples (n = 90: www.hapmap.org) and duplicates (n = 60) were genotyped across platforms for quality control purposes.All genotypes were found to be concordant with either the available online HapMap data or each other for this SNP.An exploratory factor analysis using the 60 items relating to clinical signs and symptoms from the Operational Criteria Checklist for Psychotic Illness yielded 44 items with loadings of 0.4 or more. A five factor solution gave an interpretable pattern of factors, namely manic, depressive, positive, disorganized and negative factors ( Supplementary Fig. 1, Supplementary Table 1). Factor score coefficients were then calculated in SPSS 16.0 using the regression method. There were no significant differences observed between the ZNF804A genotype groups w...

Variation in Psychosis Gene ZNF804A Is Associated With a Refined Schizotypy Phenotype but Not Neurocognitive Performance in a Large Young Male Population

“…Although the statistical evidence in schizophrenia was short of genome-wide significance, that threshold was surpassed when the phenotype was expanded to include bipolar disorder ( P = 9.96×10 –9 ). The T-allele of rs1344706 in ZNF804A , showing the strongest association signal with schizophrenia, also showed an association with bipolar disorder in the above study and predicted elevated manic symptomatology in an independent study, 2 demonstrating that variation at this locus has an effect on illness susceptibility across the traditional diagnostic boundaries. 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.…”

Association between variants of zinc finger genes and psychiatric disorders: Systematic review and meta-analysis

“…Recent studies showed that the rs1344706 T-allele was related to an increase in novel P300b amplitude, which is lower in patients than in controls (Del Re et al, 2014;O'Donoghue et al, 2014). This positive dose effect of the T-allele was also found with regard to attention, memory, language-relevant processes, and processing speed (Balog et al, 2011;Becker et al, 2012;Cummings et al, 2010;Walters et al, 2010), indicating that this risk allele may exert a protective effect on cognitive performance in schizophrenia. Interestingly, the association between rs1344706 and cognition varies with Intelligence Quotient (IQ).…”

“…Separate meta-analysis between ZNF804A rs1344706 and psychiatric disorders by ethnicity. severity mania scores on the Bipolar Affective Disorder Dimension Scale (Cummings et al, 2010). The rs1344706 variant was also implicated in suicide-attempt behavior in bipolar disorder patients (Lett et al, 2011).…”

Influence of ZNF804a on Brain Structure Volumes and Symptom Severity in Individuals With Schizophrenia

“…5 The locus was also associated with an expanded definition of the phenotype that included bipolar disorder 4 and psychosis. 1,3 Studies moving beyond diagnostic categories examined the effect of rs1344706 on quantitative phenotypic traits, including brain activation, 6,7 clinical symptomatology, 8 cognitive abilities, 7,9–11 and brain structure, 9,12 with results generally supporting an effect of the SNP on the trait of interest.…”