Language
English
Publication Date
1-1-2024
Journal
Neuroscience Applied
DOI
10.1016/j.nsa.2024.104075
PMID
40656105
PMCID
PMC12244170
PubMedCentral® Posted Date
6-7-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Schizophrenia is a complex psychiatric disorder with genetic and phenotypic heterogeneity. Accumulating rare and genome-wide association study (GWAS) common risk variant information has yet to yield robust mechanistic insight. Leveraging large-scale gene deletion mouse phenomic data thus has potential to functionally interrogate and prioritize human disease genes. To this end, we applied a cross-species network-based approach to parse an extensive mouse gene set (188 genes) associated with disrupted prepulse inhibition (PPI), a Schizophrenia endophenotype. Integrating PPI genes with high-resolution mouse and human brain transcriptomic data, we identified functional and disease coherent co-expression modules through hierarchical clustering and weighted gene co-expression network analysis (WGCNA). In two modules, Schizophrenia risk and mouse PPI genes converged based on telencephalic patterning. The associated neuronal genes were highly expressed in cingulate cortex and hippocampus; implicated in synaptic function and neurotransmission and overlapped with the greatest proportion of rare variants. Concordant neuroanatomical patterning revealed novel core Schizophrenia-relevant genes consistent with the Omnigenic hypothesis of complex traits. Among other genes discussed, the developmental and post-synaptic scaffold TANC2 (Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2) emerged from both networks as a novel core genetic driver of Schizophrenia altering PPI. Aspects of psychiatric disease comorbidity and phenotypic heterogeneity are also explored. Overall, this study provides a framework and galvanizes the value of mouse preclinical genetics and PPI to prioritize both existing and novel human Schizophrenia candidate genes as druggable targets.
Keywords
Schizophrenia, Prepulse inhibition, Endophenotype, Mouse models, Cross-species
Published Open-Access
yes
Recommended Citation
Garrett, Lillian; Trümbach, Dietrich; Lee, Donghyung; et al., "Co-Expression of Prepulse Inhibition and Schizophrenia Genes in the Mouse and Human Brain" (2024). Faculty and Staff Publications. 4031.
https://digitalcommons.library.tmc.edu/baylor_docs/4031