TY  - JOUR
AU  - Garrett, Lillian
AU  - Trumbach, Dietrich
AU  - Lee, Donghyung
AU  - Mandillo, Silvia
AU  - Samaco, Rodney
AU  - Flenniken, Ann M.
AU  - Stewart, Michelle
AU  - Aguilar-Pimental, Juan A.
AU  - Amarie, Oana V.
AU  - Becker, Lore
AU  - Calzada-Wack, Julia
AU  - Da Silva-Buttkus, Patricia
AU  - Dragano, Nathalia
AU  - Kraiger, Markus
AU  - Lengger, Christoph
AU  - Leuchtenberger, Stefanie
AU  - Marschall, Susan
AU  - Oestereicher, Manuela A.
AU  - Rathkolb, Birgit
AU  - Sanz-Moreno, Adrián
AU  - Seisenberger, Claudia
AU  - Spielmann, Nadine
AU  - Stoeger, Claudia
AU  - Kumar, Vivek
AU  - Keskivali, Piia
AU  - King, Ruairidh
AU  - Haselimashhadi, Hamed
AU  - Bezginov, Alexandr
AU  - Norris, Clare
AU  - Taylor, Sarah
AU  - Pimm, Dale
AU  - Kelsey, Lois
AU  - Berberovic, Zorana
AU  - Qu, Dawei
AU  - D'Souza, Abigail
AU  - Bradaschia, Vivian
AU  - Eskandarian, Mohammed
AU  - Shang, Xueyuan
AU  - Duffin, Kyle
AU  - Roberton, Kyle
AU  - Xu, Catherine
AU  - Baguinat, Gloria
AU  - Laurin, Valerie
AU  - Lan, Qing
AU  - Sleep, Gillian
AU  - Lintott, Lauri
AU  - Gertsenstein, Marina
AU  - Tondat, Sandra
AU  - Cruz, Maribelle
AU  - Miller, David
AU  - Bezginov, Alexandr
AU  - Sorg, Tania
AU  - Riet, Fabrice
AU  - Tolentino, Heather
AU  - Tolentino, Todd
AU  - Schuchbauer, Mike
AU  - Hockenbury, Nichole
AU  - Beeman, Karrie
AU  - Pedroia, Sheryl
AU  - Salazar, Jason
AU  - Heffner, Mollie
AU  - Hsu, Joanne
AU  - Fletcher, Colin
AU  - Vanzanten, Maya
AU  - Golini, Elisabetta
AU  - Seavitt, John R.
AU  - Lanza, Denise G.
AU  - Lorenzo, Isabel
AU  - Gaspero, Angelina
AU  - Rios, Amanda
AU  - White, Jacqueline K.
AU  - McKerlie, Colin
AU  - Nutter, Lauryl M. J.
AU  - Vukobradovic, Igor
AU  - Veeraragavan, Surabi
AU  - Yuva, Lisa
AU  - Heaney, Jason D.
AU  - Dickinson, Mary E.
AU  - Meziane, Hamid
AU  - Hérault, Yann
AU  - Wells, Sara
AU  - Lloyd, K. C. Kent
AU  - Bower, Lynette
AU  - Lanoue, Louise
AU  - Clary, Dave
AU  - Zimprich, Annemarie
AU  - Gailus-Durner, Valerie
AU  - Fuchs, Helmut
AU  - Brown, Steve D. M.
AU  - Chesler, Elissa J.
AU  - Wurst, Wolfgang
AU  - Hrabě de Angelis, Martin
AU  - Hölter, Sabine M.
TI  - Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain
JO  - Neuroscience Applied
VL  - 3
SN  - 2772-4085
CY  - Amsterdam
PB  - Elsevier
M1  - DZNE-2025-00094
SP  - 104075
PY  - 2024
AB  - 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.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1016/j.nsa.2024.104075
UR  - https://pub.dzne.de/record/275859
ER  -