Abstract
Background 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 biological processes are likely candidates to underlie schizophrenia by integrating genetic data with novel pathway analysis tools unused to date for the largest schizophrenia GWAS (N = 79,845).
Methods Using Multi-marker Analysis of GenoMic Annotation (MAGMA), we applied a primary unbiased analysis to weigh the role of biological processes from the Gene Ontology database. We subsequently evaluated these results and performed a validation analysis in MAGMA and Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA) using detailed molecular pathways from the Kyoto Encyclopedia of Genes and Genomes
Results We found enrichment of common genetic variants underlying schizophrenia in biological processes associated with synaptic signaling and neuronal differentiation. We validated enrichment of molecular signaling processes in the dopaminergic synapse, cholinergic synapse and long-term potentiation. Moreover, enrichment in these pathways was mostly driven by shared genes involved in post-synaptic membrane and downstream signaling components between these pathways.
Conclusions We 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 in schizophrenia.