Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
Julien Bryois, Nathan Skene, Thomas Folkmann Hansen, Lisette J. A. Kogelman, Hunna J. Watson, Zijing Liu, Roger A.H. Adan, Lars Alfredsson, Tetsuya Ando, Ole A. Andreassen, Jessica H. Baker, Andrew W. Bergen, Wade H. Berrettini, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Harry Brandt, Gerome Breen, Julien Bryois, Katharina Buehren, Cynthia M. Bulik, Roland Burghardt, Matteo Cassina, Sven Cichon, Maurizio Clementi, Jonathan R. I. Coleman, Roger D. Cone, Philippe Courtet, Steven Crawford, Scott J. Crow, James L. Crowley, Unna N. Danner, Oliver S. P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Dimitris Dikeos, Christian Dina, Monika Dmitrzak‐Węglarz, Elisa Docampo Martínez, Laramie E. Duncan, Karin Egberts, Stefan Ehrlich, Geòrgia Escaramís, Tõnu Esko, Xavier Estivill, Anne Farmer, Angela Favaro, Fernando Fernández‐Aranda, Manfred Fichter, Krista Fischer, Manuel Föcker, Lenka Foretová, Andreas J. Forstner, Monica Forzan, C. Franklin, Steven Gallinger, Héléna A. Gaspar, Ina Giegling, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott D. Gordon, Philip Gorwood, Monica Gratacos Mayora, Jakob Grove, Sébastien Guillaume, Yiran Guo, Håkon Håkonarson, Katherine A. Halmi, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Stefan Herms, Beate Herpertz‐Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimír Janout, Susana Jiménez‐Múrcia, Craig Johnson, Jennifer Jordan, Antonio Julià, Anders Juréus, Gursharan Kalsi, Deborah Kaminská, Allan S. Kaplan, Jaakko Kaprio
Abstract
Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.