F104. Gene Co-expression Networks Reveal Pathways of Convergence of Schizophrenia Risk Genes and of Response to Treatment
Year: 2019
Type: conference-abstract
Abstract: Schizophrenia (SCZ) is associated with genetic factors, and specific risk loci have been identified. Still, the biology and clinical translation of genetic risk remain largely unknown. Gene co-expression networks are relevant to functional and clinical translation of SCZ risk. We hypothesized that SCZ risk genes may converge into co-expression pathways which, in turn, may be associated with clinical phenotypes in SCZ patients. We used Weighted Gene Co-expression Network Analysis to identify co-expression modules in two prefrontal cortex post-mortem RNA sequencing datasets, including 379 healthy controls (HC) and 309 SCZ. We used four replication datasets (HC=339). To identify modules enriched for SCZ risk genes, we computed hypergeometric tests and corrected for multiple comparisons. To translate post mortem information into clinical phenotypes, we identified polymorphisms predicting co-expression and combined them to obtain an index approximating module co-expression (Polygenic Co-expression Index: PCI). We used two independent replication datasets (HC=131). Finally, we tested the association between PCI and treatment response in two independent SCZ cohorts (SCZ=167). We identified and replicated (all p-values<.001) a single module enriched for SCZ risk genes (13 genes in 10 loci, corrected-p-value<.001). PCI-co-expression association was replicated in two datasets (p-values<.05). PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (p-values<.05). These findings show that co-expression pathways are relevant to the neurobiology of SCZ and part of the risk genes is co-expressed in the prefrontal cortex. Results provide evidence for the clinical relevance of this co-expression pathway and its associated polymorphisms.
Source: Schizophrenia Bulletin
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2937121688