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

Schizophrenia Working Group of the Psychiatric Genomics Consortium, Stanley Global Asia Initiatives, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo LiTarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Hailiang Huang, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Kevin C. Eggan*, Kasper Lage*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Original languageEnglish
Article number106701
JournaliScience
Volume26
Issue number5
Early online date18 Apr 2023
DOIs
Publication statusPublished - 19 May 2023

Keywords / Materials (for Non-textual outputs)

  • Cellular neuroscience
  • Developmental neuroscience
  • Molecular interaction
  • Proteomics

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