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dc.contributor.authorANNEY, RICHARDen
dc.contributor.authorGILL, MICHAELen
dc.contributor.authorDONOHOE, GARYen
dc.date.accessioned2015-03-11T12:28:11Z
dc.date.available2015-03-11T12:28:11Z
dc.date.issued2014en
dc.date.submitted2014en
dc.identifier.citationNicodemus KK, Hargreaves A, Morris D, Anney R, Gill M, Corvin A, Donohoe G, Variability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway., JAMA psychiatry, 71, 7, 2014, 778-85en
dc.identifier.issn2168-622Xen
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/73538
dc.descriptionPUBLISHEDen
dc.description.abstractIMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.en
dc.description.sponsorshipRecruitment and genotyping was supported by Science Foundation Ireland (SFI) (grant 08/IN.1/B1916) and the Wellcome Trust Case Control Consortium 2 project (grants 085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (grants 072894/Z/03/Z, 090532/Z/09/Z, and 075491/Z/04/B), respectively. This publication has emanated from research conducted with the financial support of SFI and the Marie-Curie Action COFUND under grant 11/SIRG/B2183 to Dr Nicodemus. Dr Donohoe’s work is generously supported by grant funding from the Health Research Board (HRA_POR/2012/54) and SFI (12.IP.1359).en
dc.format.extent778-85en
dc.language.isoenen
dc.relation.ispartofseriesJAMA psychiatryen
dc.relation.ispartofseries71en
dc.relation.ispartofseries7en
dc.rightsYen
dc.subjectadult; allele; article; attention; bipolar disorder; cognitive defect; controlled study; episodic memory; epistasis; female; gene; gene interaction; gene replication; genetic analysis; genetic association; genetic risk; genetic susceptibility; genetic variability; human; intelligence quotient; major clinical study; major depression; male; mental performance; neuropsychological test; phenotype; polygenic score; schizoaffective psychosis; signal transduction; single nucleotide polymorphism; social cognition; training; working memory; ZNF804A geneen
dc.subject.lcshadult; allele; article; attention; bipolar disorder; cognitive defect; controlled study; episodic memory; epistasis; female; gene; gene interaction; gene replication; genetic analysis; genetic association; genetic risk; genetic susceptibility; genetic variability; human; intelligence quotient; major clinical study; major depression; male; mental performance; neuropsychological test; phenotype; polygenic score; schizoaffective psychosis; signal transduction; single nucleotide polymorphism; social cognition; training; working memory; ZNF804A geneen
dc.titleVariability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway.en
dc.typeJournal Articleen
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/anneyren
dc.identifier.peoplefinderurlhttp://people.tcd.ie/mgillen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/donoghugen
dc.identifier.rssinternalid100372en
dc.identifier.doihttp://dx.doi.org/10.1001/jamapsychiatry.2014.528en
dc.rights.ecaccessrightsopenAccess
dc.contributor.sponsorGrantNumber12.IP.1359en
dc.contributor.sponsorGrantNumber08/IN.1/B1916en


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