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

Abstract

Objectives

Schizophrenia genetics is intricate, with common and rare variants’ contributions not fully understood. Certain copy number variations (CNVs) elevate risk, pivotal for understanding mental disorder models. Despite CNVs’ genome-wide distribution and variable gene and protein effects, we must explore beyond affected genes to interaction partners and molecular pathways.

Methods

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.

Results

For CNVs that are pathogenic for schizophrenia, we found overlapping pathways, including BDNF signalling, cytoskeleton, and inflammation. Common schizophrenia risk genes identified by different studies are found in all CNV pathways, but not enriched.

Conclusions

Our findings suggest that specific pathways - BDNF signalling - 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.

Keywords:

• Schizophrenia
• copy number variations
• molecular pathways
• Brain-derivedneurotrophic factor (BDNF)
• Functional genetics

Acknowledgements

The authors would like to thank Prof. Dr. Han Brunner for helpful discussions around genetics of neurodevelopmental disorders, and Dr. Martina Kutmon and Dr. Lars Eijssen for helpful discussions around permutation testing statistics.

Statement of interest

None to declare.

Additional information

Funding

FE and CE are funded by the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N° 825575, TvAs work is supported by NIH_5U01 MH119740.