title: Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history.
abstract: Schizophrenia is a genetically and clinically heterogeneous disorder. Genetic risk factors for the disorder may differ between the sexes or between multiply affected families compared to cases with no family history. Additionally, limited data support a genetic basis for variation in onset and severity, but specific loci have not been identified. We performed genome-wide association studies (GWAS) examining genetic influences on age at onset (AAO) and illness severity as well as specific risk by sex or family history status using up to 2762 cases and 3187 controls from the International Schizophrenia Consortium (ISC). Subjects with a family history of schizophrenia demonstrated a slightly lower average AAO that was not significant following multiple testing correction (p=.048), but no differences in illness severity were observed by family history status (p=.51). Consistent with prior reports, we observed earlier AAO (p=.005) and a more severe course of illness for men (p=.002). Family history positive analyses showed the greatest association with KIF5C (p=1.96×10(-8)), however, genetic risk burden overall does not differ by family history. Separate association analyses for males and females revealed no significant sex-specific associations. The top GWAS hit for AAO was near the olfactory receptor gene OR2K2 (p=1.52×10(-7)). Analyses of illness severity (episodic vs. continuous) implicated variation in ST18 (p=8.24×10(-7)). These results confirm recognized demographic relationships but do not support a simplified genetic architecture for schizophrenia subtypes based on these variables.
authors.affiliation: Psychiatric & Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. Electronic address: sbergen@gmail.com.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Colm T
authors.initials: CT
authors.lastname: O'Dushlaine
authors.affiliation: Psychiatric & Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Phil H
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA; Washington VA Medical Center, Washington, DC, USA; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA; Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Ayman H
authors.initials: AH
authors.lastname: Fanous
authors.affiliation: Mount Sinai School of Medicine, New York, NY, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ruderfer
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Psychiatric & Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Mount Sinai School of Medicine, New York, NY, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology* / Q000235:genetics*; D012720:Severity of Illness Index; D012737:Sex Factors; D055815:Young Adult
keywords: Association; GWAS; Gender; psychosis