Document Type
Article
Publication Date
6-2024
Original Citation
Garrett L,
Trümbach D,
Lee D,
Mandillo S,
Samaco R,
Flenniken AM,
Stewart M,
,
White J,
McKerlie C,
Nutter LM,
Vukobradovic I,
Verraragavan S,
Yuva L,
Heaney JD,
Dickinson ME,
Meziane H,
Hérault Y,
Wells S,
Lloyd KK,
Bower L,
Lanaue L,
Clary D,
Zimprich A,
Gailus-Durner V,
Fuchs H,
Brown SD,
Chesler E,
Wurst W,
Hrabě de Angelis M,
Hölter SM.
Co-expression of prepulse inhibition and schizophrenia genes in the mouse and human brain Neuroscience Applied. 2024;3:104075.
Keywords
JMG
JAX Source
Neuroscience Applied. 2024;3:104075.
ISSN
2772-4085
DOI
https://doi.org/10.1016/j.nsa.2024.104075
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. As- pects 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.
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