RT Journal Article
SR Electronic
T1 Comprehensive pathway analyses of schizophrenia risk loci point to dysfunctional postsynaptic signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 117481
DO 10.1101/117481
A1 Dick Schijven
A1 Daniel Kofink
A1 Vinicius Tragante
A1 Marloes Verkerke
A1 Sara L. Pulit
A1 René S. Kahn
A1 Jan H. Veldink
A1 Christiaan H. Vinkers
A1 Marco P. Boks
A1 Jurjen J. Luykx
YR 2017
UL http://biorxiv.org/content/early/2017/03/17/117481.abstract
AB 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.