Journal Article

DZNE-2025-00094

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Garrett, L. ; Trumbach, D. ; Lee, D. ; Mandillo, S. ; Samaco, R. ; Flenniken, A. M. ; Stewart, M. ; Aguilar-Pimental, J. A. ; Amarie, O. V. ; Becker, L. ; Calzada-Wack, J. ; Da Silva-Buttkus, P. ; Dragano, N. ; Kraiger, M. ; Lengger, C. ; Leuchtenberger, S. ; Marschall, S. ; Oestereicher, M. A. ; Rathkolb, B. ; Sanz-Moreno, A. ; Seisenberger, C. ; Spielmann, N. ; Stoeger, C. ; Kumar, V. ; Keskivali, P. ; King, R. ; Haselimashhadi, H. ; Bezginov, A. ; Norris, C. ; Taylor, S. ; Pimm, D. ; Kelsey, L. ; Berberovic, Z. ; Qu, D. ; D'Souza, A. ; Bradaschia, V. ; Eskandarian, M. ; Shang, X. ; Duffin, K. ; Roberton, K. ; Xu, C. ; Baguinat, G. ; Laurin, V. ; Lan, Q. ; Sleep, G. ; Lintott, L. ; Gertsenstein, M. ; Tondat, S. ; Cruz, M. ; Miller, D. ; Bezginov, A. ; Sorg, T. ; Riet, F. ; Tolentino, H. ; Tolentino, T. ; Schuchbauer, M. ; Hockenbury, N. ; Beeman, K. ; Pedroia, S. ; Salazar, J. ; Heffner, M. ; Hsu, J. ; Fletcher, C. ; Vanzanten, M. ; Golini, E. ; Seavitt, J. R. ; Lanza, D. G. ; Lorenzo, I. ; Gaspero, A. ; Rios, A. ; 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.DZNE* ; Hrabě de Angelis, M. ; Hölter, S. M.

2024
Elsevier Amsterdam

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Please use a persistent id in citations: doi: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. 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.

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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