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@ARTICLE{Garrett:275859,
author = {Garrett, Lillian and Trumbach, Dietrich and Lee, Donghyung
and Mandillo, Silvia and Samaco, Rodney and Flenniken, Ann
M. and Stewart, Michelle and Aguilar-Pimental, Juan A. and
Amarie, Oana V. and Becker, Lore and Calzada-Wack, Julia and
Da Silva-Buttkus, Patricia and Dragano, Nathalia and
Kraiger, Markus and Lengger, Christoph and Leuchtenberger,
Stefanie and Marschall, Susan and Oestereicher, Manuela A.
and Rathkolb, Birgit and Sanz-Moreno, Adrián and
Seisenberger, Claudia and Spielmann, Nadine and Stoeger,
Claudia and Kumar, Vivek and Keskivali, Piia and King,
Ruairidh and Haselimashhadi, Hamed and Bezginov, Alexandr
and Norris, Clare and Taylor, Sarah and Pimm, Dale and
Kelsey, Lois and Berberovic, Zorana and Qu, Dawei and
D'Souza, Abigail and Bradaschia, Vivian and Eskandarian,
Mohammed and Shang, Xueyuan and Duffin, Kyle and Roberton,
Kyle and Xu, Catherine and Baguinat, Gloria and Laurin,
Valerie and Lan, Qing and Sleep, Gillian and Lintott, Lauri
and Gertsenstein, Marina and Tondat, Sandra and Cruz,
Maribelle and Miller, David and Bezginov, Alexandr and Sorg,
Tania and Riet, Fabrice and Tolentino, Heather and
Tolentino, Todd and Schuchbauer, Mike and Hockenbury,
Nichole and Beeman, Karrie and Pedroia, Sheryl and Salazar,
Jason and Heffner, Mollie and Hsu, Joanne and Fletcher,
Colin and Vanzanten, Maya and Golini, Elisabetta and
Seavitt, John R. and Lanza, Denise G. and Lorenzo, Isabel
and Gaspero, Angelina and Rios, Amanda and White, Jacqueline
K. and McKerlie, Colin and Nutter, Lauryl M. J. and
Vukobradovic, Igor and Veeraragavan, Surabi and Yuva, Lisa
and Heaney, Jason D. and Dickinson, Mary E. and Meziane,
Hamid and Hérault, Yann and Wells, Sara and Lloyd, K. C.
Kent and Bower, Lynette and Lanoue, Louise and Clary, Dave
and Zimprich, Annemarie and Gailus-Durner, Valerie and
Fuchs, Helmut and Brown, Steve D. M. and Chesler, Elissa J.
and Wurst, Wolfgang and Hrabě de Angelis, Martin and
Hölter, Sabine M.},
title = {{C}o-expression of prepulse inhibition and {S}chizophrenia
genes in the mouse and human brain},
journal = {Neuroscience Applied},
volume = {3},
issn = {2772-4085},
address = {Amsterdam},
publisher = {Elsevier},
reportid = {DZNE-2025-00094},
pages = {104075},
year = {2024},
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.},
cin = {AG Wurst},
cid = {I:(DE-2719)1140001},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
doi = {10.1016/j.nsa.2024.104075},
url = {https://pub.dzne.de/record/275859},
}