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Garrett, L. ; Trümbach, D. ; Lee, D.* ; Mandillo, S.* ; Samaco, R.C.* ; Flenniken, A.M.* ; Stewart, M.* ; White, J.K.* ; McKerlie, C.* ; Nutter, L.M.J.* ; Vukobradovic, I.* ; Veeraragavan, S.* ; Yuva, L.* ; Heaney, J.D.* ; Dickinson, M.E.* ; Meziane, H.* ; Hérault, Y.* ; Wells, S.* ; Lloyd, K.C.K.* ; Bower, L.* ; Lanoue, L.* ; Clary, D.* ; Zimprich, A. ; Gailus-Durner, V. ; Fuchs, H. ; Brown, S.D.M.* ; Chesler, E.J.* ; Wurst, W. ; Hrabě de Angelis, M. ; Hölter, S.M.

Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain.

Neurosci. App. 3:104075 (2024)

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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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