TY - JOUR T1 - Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling JF - bioRxiv DO - 10.1101/117481 SP - 117481 AU - Dick Schijven AU - Daniel Kofink AU - Vinicius Tragante AU - Marloes Verkerke AU - Sara L. Pulit AU - René S. Kahn AU - Jan H. Veldink AU - Christiaan H. Vinkers AU - Marco P. Boks AU - Jurjen J. Luykx Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/03/17/117481.abstract N2 - Large-scale genome-wide association studies (GWAS) have implicated many low-penetrance loci in schizophrenia, but have yielded limited insight into disease pathophysiology. This limited understanding of the etiology of schizophrenia hampers the development of novel pharmacological treatments. Pathway and gene set analyses may provide biological context to genome-wide data and carry the potential to generate hypotheses about disease mechanisms and leads for novel drug discovery. We aimed to examine which neurobiological processes are likely candidates to underlie schizophrenia by integrating genetic data with existing pathway analysis tools in a comprehensive bioinformatics pipeline. Using unbiased pathway analysis methods to weigh the role of biological processes in schizophrenia, we demonstrate enrichment of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in pathways and gene sets associated with synaptic functioning. We subsequently performed targeted analyses of neurotransmitter gene sets, through which we detected enrichment of gene sets representing the dopaminergic synapse, cholinergic synapse and long-term potentiation. We furthermore highlight that enrichment is mostly located in postsynaptic membrane and postsynaptic signaling components. We thus provide the strongest genetics-informed evidence to date that dysfunctional postsynaptic pathways are implicated in schizophrenia. Future studies in both preclinical and clinical settings may further disentangle these systems to allow the development of new treatment options to target core symptoms in schizophrenia. ER -