Consensus molecular environment of schizophrenia risk genes in coexpression networks shifting across age and brain regions

Giulio Pergola, Madhur Parihar, Leonardo Sportelli, Rahul Bharadwaj, Christopher Borcuk, Eugenia Radulescu, Loredana Bellantuono, Giuseppe Blasi, Qiang Chen, Joel E. Kleinman, Yanhong Wang, Srinidhi Rao Sripathy, Brady Maher, Alfonso Monaco, Fabiana Rossi, Joo Heon Shin, Thomas Hyde, Alessandro Bertolino, Daniel Weinberger

Research output: Contribution to journalArticlepeer-review

Abstract

Schizophrenia is a neurodevelopmental brain disorder whose genetic risk is associated with shifting clinical phenomena across the life span. We investigated the convergence of putative schizophrenia risk genes in brain coexpression networks in postmortem human prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and dentate gyrus granule cells, parsed by specific age periods (total N = 833). The results support an early prefrontal involvement in the biology underlying schizophrenia and reveal a dynamic interplay of regions in which age parsing explains more variance in schizophrenia risk compared to lumping all age periods together. Across multiple data sources and publications, we identify 28 genes that are the most consistently found partners in modules enriched for schizophrenia risk genes in DLPFC; twenty-three are previously unidentified associations with schizophrenia. In iPSC-derived neurons, the relationship of these genes with schizophrenia risk genes is maintained. The genetic architecture of schizophrenia is embedded in shifting coexpression patterns across brain regions and time, potentially underwriting its shifting clinical presentation.

Original languageEnglish (US)
Article numbereade2812
JournalScience Advances
Volume9
Issue number15
DOIs
StatePublished - Apr 2023

ASJC Scopus subject areas

  • General

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