Expanding the range of ZNF804A variants conferring risk of psychosis

Steinberg, Stacy; Mors, Ole; Børglum, Anders D.; Gústafsson, Ómar; Werge, Thomas; Mortensen, Preben Bo; Andreassen, Ole A.; Sigurðsson, Engilbert; Thorgeirsson, Thorgeir E.; Böttcher, Yvonne; Olason, Pall I.; Ophoff, Roel A.; Cichon, Sven; Gudjonsdottir, Iris H; Pietiläinen, Olli; Nyegaard, Mette; Tuulio-Henriksson, A; Ingason, Andrés; Hansen, Thomas; Athanasiu, Lavinia; Suvisaari, Jaana; Lönnqvist, Jouko; Paunio, Tiina; Hartmann, Annette M.; Jürgens, Gesche; Nordentoft, Merete; Hougaard, David M.; Nørgaard‐Pedersen, Bent; Breuer, René; Møller, Henrik; Giegling, Ina; Glenthøj, Birte; Rasmussen, Henrik Berg; Mattheisen, Manuel; Bitter, István; Réthelyi, János; Sigmundsson, Thordur; Fossdal, Ragnheiður; Þorsteinsdóttir, Unnur; Ruggeri, Mirella; Tosato, Sarah; Strengman, Eric; Kiemeney, Lambertus A.; Melle, Ingrid; Djurovic, Srdjan; Абрамова, Л. И.; Kaleda, V.; Walshe, Muriel; Bramon, Elvira; Vassos, Evangelos; Li, T; Fraser, G. T.; Walker, Nicholas; Toulopoulou, T.; Yoon, Joeng Lim; Freimer, Nelson B.; Cantor, Rita M.; Murray, Robin M.; Kong, Augustine; Голимбет, В. Е.; Jönsson, Erik G.; Terenius, Lars; Agartz, Ingrid; Pétursson, Hannes; Nöthen, Markus M.; Rietschel, Marcella; Peltonen, Leena; Rujescu, Dan; Collier, David; Stefánsson, Hreinn; Clair, David St; Stefánsson, Kāri

doi:10.1038/mp.2009.149

Cited by 146 publications

(134 citation statements)

References 45 publications

(53 reference statements)

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“…Consistent with previous studies (Riley et al, 2010;Williams et al, 2011;Steinberg et al, 2011;Zhang et al, 2011;Xiao et al, 2011, see Li et al, 2011, for an exception), the current study found evidence for the association between rs1344706 and schizophrenia. In addition, we replicated results of Walters et al (2010) that the association between rs1344706 and schizophrenia became stronger when the samples were limited to those with relatively high IQ.…”

Section: Discussionsupporting

confidence: 81%

“…Recently, an intronic SNP in this gene, rs1344706, has been found to be one of the most compelling candidate SNPs for schizophrenia. As shown by a recent whole genome study (O'Donovan et al, 2008) and several follow-up replications (Riley et al, 2010;Williams et al, 2011;Steinberg et al, 2011), there is a strong association between this SNP and schizophrenia with the A allele being the risk allele. This association has also been replicated among Han Chinese population in two studies Xiao et al, 2011) but not a third one .…”

Section: Introductionmentioning

confidence: 99%

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Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Chen

Zhai

et al. 2012

Neuropsychopharmacol

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ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Chen

Zhai

et al. 2012

Neuropsychopharmacol

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“…Despite being relatively under-powered to replicate such a modest effect, two of three recently reported large SZ GWAS studies (Purcell et al, 2009;Sullivan et al, 2008) and a discrete replication study by Riley et al (2009) supported association between the same risk allele and increased SZ risk. Copy number variation at this locus has also been identified for psychosis (Steinberg et al, 2010). The protein encoded by ZNF804A is uncharacterized, but given its zinc finger domain, is likely to have a role in regulating gene expression.…”

Section: Introductionmentioning

confidence: 99%

ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia

et al. 2011

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ZNF804A rs1344706 is the first genetic risk variant to achieve genome wide significance for psychosis. Following earlier evidence that patients carrying the ZNF804A risk allele had relatively spared memory function compared to patient non-carriers, we investigated whether ZNF804A was also associated with variation in brain volume. In a sample of 70 patients and 38 healthy participants we used voxel based morphometry to compare homozygous (AA) carriers of the ZNF804A risk allele to heterozygous and homozygous (AC/CC) non-carriers for both whole brain volume and specific regions implicated in earlier ZNF804A studies-the dorsolateral pre-frontal cortex, the hippocampus, and the amygdala. For patients, but not for controls, we found that homozygous 'AA' risk carriers had relatively larger gray matter volumes than heterozygous/homozygous non-carriers (AC/CC), particularly for hippocampal volumes. These data are consistent with our earlier behavioral data and suggest that ZNF804A is delineating a schizophrenia subtype characterized by relatively intact brain volume. Establishing if this represents a discrete molecular pathogenesis with consequences for nosology and treatment will be an important next step in understanding ZNF084A's role in illness risk.

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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).

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confidence: 99%

Clinical symptomatology and the psychosis risk gene ZNF804A

Cummings

Donohoe

McDonald

et al. 2010

Schizophrenia Research

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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...

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Expanding the range of ZNF804A variants conferring risk of psychosis

Cited by 146 publications

References 45 publications

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia

Clinical symptomatology and the psychosis risk gene ZNF804A

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