title: Genome-wide gene pathway analysis of psychotic illness symptom dimensions based on a new schizophrenia-specific model of the OPCRIT.
abstract: Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses. Using an Irish family sample, this study 1) factor analyzed clinician-rated Operational Criteria Checklist items in cases with schizophrenia only, 2) scored the full sample based on these factor loadings, and 3) implemented genome-wide association, gene-based, and gene-pathway analysis of these SCZ-based symptom factors (final N=507). Three factors emerged from the analysis of the schizophrenia cases: a manic, a depressive, and a positive symptom factor. In gene-based analyses of these factors, multiple genes had q<0.01. Of particular interest are findings for PTPRG and WBP1L, both of which were previously implicated by the Psychiatric Genomics Consortium study of SCZ; results from this study suggest that variants in these genes might also act as modifiers of SCZ symptoms. Gene pathway analyses of the first factor indicated over-representation of glutamatergic transmission, GABA-A receptor, and cyclic GMP pathways. Results suggest that these pathways may have differential influence on affective symptom presentation in schizophrenia.
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA. Electronic address: ardocherty@vcu.edu.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Docherty
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: T Bernard
authors.initials: TB
authors.lastname: Bigdeli
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Edwards
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Silviu
authors.initials: S
authors.lastname: Bacanu
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Donghyung
authors.initials: D
authors.lastname: Lee
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Neale
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Wormley
authors.affiliation: Queen's University, Belfast, Ireland.
authors.forename: Dermot
authors.initials: D
authors.lastname: Walsh
authors.affiliation: Center for Public Health, Belfast, Ireland.
authors.forename: F Anthony
authors.initials: FA
authors.lastname: O'Neill
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Brien P
authors.initials: BP
authors.lastname: Riley
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth, University School of Medicine, VA, USA; Washington Veterans Affairs Healthcare System, Washington D.C. USA; Georgetown University School of Medicine, Washington D.C. USA.
authors.forename: Ayman H
authors.initials: AH
authors.lastname: Fanous
mesh_terms: D005163:Factor Analysis, Statistical; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011618:Psychotic Disorders / Q000209:etiology* / Q000235:genetics*; D012559:Schizophrenia / Q000150:complications* / Q000175:diagnosis
keywords: Dimensional assessment; Gene enrichment; Gene pathway; Genetic; Modifier gene; OPCRIT; Schizophrenia; Symptoms