Integrating rare variant genetics and brain transcriptome data implicates novel schizophrenia putative risk genes.

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• The genetic basis of schizophrenia is complex and polygenic.
• Genome-wide association studies (GWAS) have identified numerous schizophrenia risk loci.
• Rare variants also contribute significantly to schizophrenia risk, as indicated by SCHEMA study results.

Purpose of the Study:

• To identify novel schizophrenia risk genes by integrating genetic and transcriptomic data.
• To enhance the power of discovering new risk genes beyond existing GWAS and SCHEMA findings.

Main Methods:

• Integrated genetic data from Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) with transcriptome data from BrainSpan.
• Utilized the multi-omics integration tool DAWN to identify putative schizophrenia risk genes.
• Performed Gene Ontology (GO) and SynGO functional enrichment analyses on identified genes.

Main Results:

• Identified 47 putative schizophrenia risk genes, including 19 newly discovered genes, with a false discovery rate (FDR) < 5%.
• Nearly all previously identified SCHEMA risk genes were included in the 47 putative risk genes.
• Functional enrichment analysis revealed significant enrichment in cell-to-cell signaling, communication, and transporter functions.
• SynGO analysis indicated enrichment in pre-synapse, synapse, and post-synapse, supporting the role of synaptic function in schizophrenia.

Conclusions:

• The integration of multi-omics data effectively identified novel schizophrenia risk genes.
• The identified genes are implicated in synaptic functions, aligning with the two-hit hypothesis of schizophrenia.
• Further research into these identified genes can elucidate schizophrenia etiology and inform therapeutic strategies.