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Schizophr Res DOI:10.1016/j.schres.2014.01.030

Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history.

Publication TypeJournal Article
Year of Publication2014
AuthorsBergen, SE, O'Dushlaine, CT, Lee, PH, Fanous, AH, Ruderfer, DM, Ripke, S, Sullivan, PF, Smoller, JW, Purcell, SM, Corvin, A
Corporate AuthorsInternational Schizophrenia Consortium, Swedish Schizophrenia Consortium
JournalSchizophr Res
Date Published2014 Apr
KeywordsAdolescent, Adult, Age of Onset, Child, Family, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Risk Factors, Schizophrenia, Severity of Illness Index, Sex Factors, Young Adult

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.


Alternate JournalSchizophr. Res.
PubMed ID24581549
PubMed Central IDPMC4422643
Grant ListK99 MH101367 / MH / NIMH NIH HHS / United States
R01 MH079799 / MH / NIMH NIH HHS / United States
MH079799 / MH / NIMH NIH HHS / United States