title: Integration of gene expression and GWAS results supports involvement of calcium signaling in Schizophrenia.
abstract: The number of Genome Wide Association Studies (GWAS) of schizophrenia is rapidly growing. However, the small effect of individual genes limits the number of reliably implicated genes, which are too few and too diverse to perform reliable pathway analysis; hence the biological roles of the genes implicated in schizophrenia are unclear. To overcome these limitations we combine GWAS with genome-wide expression data from human post-mortem brain samples of schizophrenia patients and controls, taking these steps: 1) Identify 36 GWAS-based genes which are expressed in our dataset. 2) Find a cluster of 19 genes with highly correlated expression. We show that this correlation pattern is robust and statistically significant. 3) GO-enrichment analysis of these 19 genes reveals significant enrichment of ion channels and calcium-related processes. This finding (based on analyzing a small number of coherently expressed genes) is validated and enhanced in two ways: First, the emergence of calcium channels and calcium signaling is corroborated by identifying proteins that interact with those encoded by the cluster of 19. Second, extend the 19 cluster genes into 1028 genes, whose expression is highly correlated with the cluster's average profile. When GO-enrichment analysis is performed on this extended set, many schizophrenia related pathways appear, with calcium-related processes enriched with high statistical significance. Our results give further, expression-based validation to GWAS results, support a central role of calcium-signaling in the pathogenesis of schizophrenia, and point to additional pathways potentially related to the disease.
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; The Emotion-Cognition Research Center, Shalvata Mental Health Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Hertzberg
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Katsel
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA; Department of Psychiatry, James J Peters VA Medical Center, Bronx, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel. Electronic address: Eytan.domany@weizmann.ac.il.
authors.forename: E
authors.initials: E
authors.lastname: Domany
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020013:Calcium Signaling / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D013223:Statistics as Topic
keywords: GWAS; Gene expression; Pathway analysis