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

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

Journal

Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320

Informations de publication

Date de publication:
31 Aug 2024
Historique:
received: 08 11 2023
revised: 03 04 2024
accepted: 07 08 2024
medline: 6 9 2024
pubmed: 6 9 2024
entrez: 5 9 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.neuron.2024.08.005 PMID: 39236717
pubmed: 39236717
pii: S0896-6273(24)00575-0
doi: 10.1016/j.neuron.2024.08.005
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests A.B. received consulting fees by Biogen and lecture fees by Otsuka, Janssen, and Lundbeck. D.R.W. serves on the scientific advisory boards of Sage Therapeutics and Pasithea Therapeutics. G.P. received lecture fees by Lundbeck.

Auteurs

Christopher Borcuk (C)

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.

Madhur Parihar (M)

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Leonardo Sportelli (L)

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.

Joel E Kleinman (JE)

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.

Joo Heon Shin (JH)

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Thomas M Hyde (TM)

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.

Alessandro Bertolino (A)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.

Daniel R Weinberger (DR)

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: drweinberger@libd.org.

Giulio Pergola (G)

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: giulio.pergola@libd.org.

Classifications MeSH