title: Protein Interaction Networks Link Schizophrenia Risk Loci to Synaptic Function.
abstract: Schizophrenia is a severe and highly heritable psychiatric disorder affecting approximately 1% of the population. Genome-wide association studies have identified 108 independent genetic loci with genome-wide significance but their functional importance has yet to be elucidated. Here, we develop a novel strategy based on network analysis of protein-protein interactions (PPI) to infer biological function associated with variants most strongly linked to illness risk. We show that the schizophrenia loci are strongly linked to synaptic transmission (PFWE< .001) and ion transmembrane transport (PFWE= .03), but not to ontological categories previously found to be shared across psychiatric illnesses. We demonstrate that brain expression of risk-linked genes within the identified processes is strongly modulated during birth and identify a set of synaptic genes consistently changed across multiple brain regions of adult schizophrenia patients. These results suggest synaptic function as a developmentally determined schizophrenia process supported by the illness's most associated genetic variants and their PPI networks. The implicated genes may be valuable targets for mechanistic experiments and future drug development approaches.
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Schwarz
authors.affiliation: Vencore Labs, Basking Ridge, NJ.
authors.forename: Rauf
authors.initials: R
authors.lastname: Izmailov
authors.affiliation: Computer Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Liò
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
mesh_terms: D002540:Cerebral Cortex / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D056426:Genetic Loci; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics*
keywords: GWAS; functional analysis; genetics; pathway analysis