A Systems-Level Investigation into the Genetic Determinants of Childhood-Onset Schizophrenia
Open AccessBackground: Schizophrenia is a neurodevelopmental disorder affecting ~1% of the population. Indicators include auditory hallucinations, delusions, disorganized and unusual thinking and speech, and social isolation due to impairment in social cognition, paranoia, and general avolition. The average age of onset is 25 in females and 18 in males but it occurs younger in rare instances. Schizophrenic children share symptoms with adult counterparts and those diagnosed with autism and other pervasive developmental disabilities.Objectives: To date, several putative schizophrenia susceptibility genes have been identified but the complex nature of the disease complicates the overall picture. Systems-level analysis and the identification of core molecular pathways are lacking. Additionally, a comparison of the genes and pathways affected by schizophrenia to autism may yield insight into neurological diseases as a whole.Methods: Illumina microarray expression data was analyzed from 86 childhood-onset schizophrenia cases and 72 healthy siblings. A mixed-model ANOVA eliminated confounding factors (age, sex, race, and array/scan date). Subsequently, cases and controls were grouped in different ways and 2-class t-tests revealed gene sets that significantly differentiated the schizophrenia patients from healthy individuals. These genes were analyzed using Ingenuity Pathway Analysis and Ariadne Pathway Studio 5.Results: First, significant differentially expressed genes were identified between all cases and controls; most were novel. Pathways implicated by these genes reflected neurological and sugar metabolism functions as major themes. Secondly, PCA and HCL led to the discovery of three distinct schizophrenia groups, possibly correlating with disease phenotypes or severity of specific symptoms. ~20% of the genes found in analyses 1 and 2 (68/313; 280/ 1554) overlap with differentially expressed genes between autism case-controls identified independently in our laboratory. A third analysis investigated sib-pairs and also detected detrimental impact on the nervous system and sugar-processing.Conclusions: This study uncovers new potential schizophrenia susceptibility genes and lends insight into pathways affected in abnormal development leading to schizophrenia and other neurological diseases. These pathways also explain the co-morbidity of diabetes and epilepsy observed in the literature. Furthermore, the study suggests a possible way to classify biological subtypes of schizophrenia on the basis of gene expression profiles.
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