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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.

SUBMITTER: Bergen SE

PROVIDER: S-EPMC4422643 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Bergen Sarah E SE O'Dushlaine Colm T CT Lee Phil H PH Fanous Ayman H AH Ruderfer Douglas M DM Ripke Stephan S Sullivan Patrick F PF Smoller Jordan W JW Purcell Shaun M SM Corvin Aiden A

Schizophrenia research 20140226 1-3

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 ...[more]

PMID: 24581549

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Project description:BackgroundGenome-wide association studies have identified numerous single nucleotide polymorphisms associated with type 2 diabetes through the past years. In previous studies, the usefulness of these genetic markers for prediction of diabetes was found to be limited. However, differences may exist between substrata of the population according to the presence of major diabetes risk factors. This study aimed to investigate the added predictive value of genetic information (42 single nucleotide polymorphisms) in subgroups of sex, age, family history of diabetes, and obesity.MethodsA case-cohort study (random subcohort N?=?1,968; incident cases: N?=?578) within the European Prospective Investigation into Cancer and Nutrition Potsdam study was used. Prediction models without and with genetic information were evaluated in terms of the area under the receiver operating characteristic curve and the integrated discrimination improvement. Stratified analyses included subgroups of sex, age (<50 or ?50 years), family history (positive if either father or mother or a sibling has/had diabetes), and obesity (BMI< or ?30 kg/m(2)).ResultsA genetic risk score did not improve prediction above classic and metabolic markers, but - compared to a non-invasive prediction model - genetic information slightly improved the area under the receiver operating characteristic curve (difference [95%-CI]: 0.007 [0.002-0.011]). Stratified analyses showed stronger improvement in the older age group (0.010 [0.002-0.018]), the group with a positive family history (0.012 [0.000-0.023]) and among obese participants (0.015 [-0.005-0.034]) compared to the younger participants (0.005 [-0.004-0.014]), participants with a negative family history (0.003 [-0.001-0.008]) and non-obese (0.007 [0.000-0.014]), respectively. No difference was found between men and women.ConclusionThere was no incremental value of genetic information compared to standard non-invasive and metabolic markers. Our study suggests that inclusion of genetic variants in diabetes risk prediction might be useful for subgroups with already manifest risk factors such as older age, a positive family history and obesity.

Dataset Information

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

Publications

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

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