Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk.
Neuron
; 2024 Aug 31.
Article
in En
| MEDLINE
| ID: mdl-39236717
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Neuron
Journal subject:
NEUROLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Italy
Country of publication:
United States