Copy number variant risk loci for schizophrenia converge on the BDNF pathway

Schizophrenia genetics is complex, and the contribution of common and rare variants are not fully understood. Several specific copy number variations (CNVs) confer increased risk, and the study of their effects is central to molecular models of mental disorders. However, these CNVs are spread across the genome and differ in the number of genes affected and classes of coded proteins. This diversity suggests that we need to look beyond the deleted or duplicated genes, to their interaction partners and involved molecular pathways. In this study, we developed machine-readable interactive pathways to enable analysis of functional effects of genes within CNV loci and identify ten common pathways across CNVs with high schizophrenia risk using the WikiPathways database, schizophrenia risk gene collections from GWAS studies, and a gene-disease association database. For CNVs that are pathogenic for schizophrenia, we found overlapping pathways, including BDNF signaling, cytoskeleton, and inflammation. Common schizophrenia risk genes identified by different studies are found in all CNV pathways, but not enriched. Our findings suggest that specific pathways - BDNF signaling - are critical contributors to schizophrenia risk conferred by rare CNVs. Our approach highlights the importance of not only investigating deleted or duplicated genes within pathogenic CNV loci, but also study their direct interaction partners, which may explain pleiotropic effects of CNVs on schizophrenia risk and offer a broader field for interventions.