Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk

Christopher Borcuk; Madhur Parihar; Leonardo Sportelli; Joel E Kleinman; Joo Heon Shin; Thomas M Hyde; Alessandro Bertolino; Daniel R Weinberger; Giulio Pergola

doi:10.1016/j.neuron.2024.08.005

Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk

Neuron. 2024 Nov 6;112(21):3551-3566.e6. doi: 10.1016/j.neuron.2024.08.005. Epub 2024 Sep 4.

Authors

Christopher Borcuk¹, Madhur Parihar², Leonardo Sportelli¹, Joel E Kleinman³, Joo Heon Shin², Thomas M Hyde⁴, Alessandro Bertolino⁵, Daniel R Weinberger⁶, Giulio Pergola⁷

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
² Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
³ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.
⁶ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].
⁷ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].

PMID: 39236717
DOI: 10.1016/j.neuron.2024.08.005

Abstract

The omnigenic model posits that genetic risk for traits with complex heritability involves cumulative effects of peripheral genes on mechanistic "core genes," suggesting that in a network of genes, those closer to clusters including core genes should have higher GWAS signals. In gene co-expression networks, we confirmed that GWAS signals accumulate in genes more connected to risk-enriched gene clusters, highlighting across-network risk convergence. This was strongest in adult psychiatric disorders, especially schizophrenia (SCZ), spanning 70% of network genes, suggestive of super-polygenic architecture. In snRNA-seq cell type networks, SCZ risk convergence was strongest in L2/L3 excitatory neurons. We prioritized genes most connected to SCZ-GWAS genes, which showed robust association to a CRISPRa measure of PGC3 regulation and were consistently identified across several brain regions. Several genes, including dopamine-associated ones, were prioritized specifically in the striatum. This strategy thus retrieves current drug targets and can be used to prioritize other potential drug targets.

Keywords: MAGMA; RNA sequencing; gene co-expression networks; genetic risk; heritability; omnigenic model; postmortem brain; psychiatric disorders; schizophrenia; trans-eQTLs.

MeSH terms

Gene Regulatory Networks* / genetics
Genetic Predisposition to Disease* / genetics
Genome-Wide Association Study*
Humans
Multifactorial Inheritance / genetics
Schizophrenia* / genetics
Schizophrenia* / metabolism