%0 Journal Article
%A Garrett, Lillian
%A Trumbach, Dietrich
%A Lee, Donghyung
%A Mandillo, Silvia
%A Samaco, Rodney
%A Flenniken, Ann M.
%A Stewart, Michelle
%A Aguilar-Pimental, Juan A.
%A Amarie, Oana V.
%A Becker, Lore
%A Calzada-Wack, Julia
%A Da Silva-Buttkus, Patricia
%A Dragano, Nathalia
%A Kraiger, Markus
%A Lengger, Christoph
%A Leuchtenberger, Stefanie
%A Marschall, Susan
%A Oestereicher, Manuela A.
%A Rathkolb, Birgit
%A Sanz-Moreno, Adrián
%A Seisenberger, Claudia
%A Spielmann, Nadine
%A Stoeger, Claudia
%A Kumar, Vivek
%A Keskivali, Piia
%A King, Ruairidh
%A Haselimashhadi, Hamed
%A Bezginov, Alexandr
%A Norris, Clare
%A Taylor, Sarah
%A Pimm, Dale
%A Kelsey, Lois
%A Berberovic, Zorana
%A Qu, Dawei
%A D'Souza, Abigail
%A Bradaschia, Vivian
%A Eskandarian, Mohammed
%A Shang, Xueyuan
%A Duffin, Kyle
%A Roberton, Kyle
%A Xu, Catherine
%A Baguinat, Gloria
%A Laurin, Valerie
%A Lan, Qing
%A Sleep, Gillian
%A Lintott, Lauri
%A Gertsenstein, Marina
%A Tondat, Sandra
%A Cruz, Maribelle
%A Miller, David
%A Bezginov, Alexandr
%A Sorg, Tania
%A Riet, Fabrice
%A Tolentino, Heather
%A Tolentino, Todd
%A Schuchbauer, Mike
%A Hockenbury, Nichole
%A Beeman, Karrie
%A Pedroia, Sheryl
%A Salazar, Jason
%A Heffner, Mollie
%A Hsu, Joanne
%A Fletcher, Colin
%A Vanzanten, Maya
%A Golini, Elisabetta
%A Seavitt, John R.
%A Lanza, Denise G.
%A Lorenzo, Isabel
%A Gaspero, Angelina
%A Rios, Amanda
%A White, Jacqueline K.
%A McKerlie, Colin
%A Nutter, Lauryl M. J.
%A Vukobradovic, Igor
%A Veeraragavan, Surabi
%A Yuva, Lisa
%A Heaney, Jason D.
%A Dickinson, Mary E.
%A Meziane, Hamid
%A Hérault, Yann
%A Wells, Sara
%A Lloyd, K. C. Kent
%A Bower, Lynette
%A Lanoue, Louise
%A Clary, Dave
%A Zimprich, Annemarie
%A Gailus-Durner, Valerie
%A Fuchs, Helmut
%A Brown, Steve D. M.
%A Chesler, Elissa J.
%A Wurst, Wolfgang
%A Hrabě de Angelis, Martin
%A Hölter, Sabine M.
%T Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain
%J Neuroscience Applied
%V 3
%@ 2772-4085
%C Amsterdam
%I Elsevier
%M DZNE-2025-00094
%P 104075
%D 2024
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%R 10.1016/j.nsa.2024.104075
%U https://pub.dzne.de/record/275859