Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Genetic studies have identified numerous schizophrenia risk genes, with overlaps observed between schizophrenia and neurodevelopmental disorders.
• Functional interpretation of these risk genes within specific brain cell types remains a significant challenge.

Purpose of the Study:

• To functionally interpret schizophrenia risk genes by examining their protein interaction networks in human cortical neurons.
• To establish a cell-type-specific interactome framework for understanding genetic and transcriptomic data in schizophrenia and related disorders.

Main Methods:

• Interaction proteomics was performed on six schizophrenia risk genes implicated in neurodevelopment, using human induced cortical neurons.
• Network analysis was integrated with genetic data, including common variant risk (GWAS, eQTL), and rare mutation data.

Main Results:

• The identified protein network is enriched for common variant schizophrenia risk in European and East Asian populations.
• This network is down-regulated in layer 5/6 cortical neurons from individuals with schizophrenia.
• A sub-network involving HCN1, HCN4, and AKAP11 showed enrichment for both common variant risk and rare mutations in schizophrenia and bipolar disorder.

Conclusions:

• Brain cell-type-specific interactomes provide a valuable framework for interpreting genetic and transcriptomic findings in schizophrenia.
• This approach can prioritize additional genes within genome-wide association study (GWAS) loci.
• The study highlights the role of specific protein networks in the pathophysiology of schizophrenia and related neurodevelopmental disorders.