Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease

Julien Bryois, Nathan G. Skene, Thomas Folkmann Hansen, Lisette J.A. Kogelman, Hunna J. Watson, Zijing Liu, Roger Adan, Lars Alfredsson, Tetsuya Ando, Ole Andreassen, Jessica Baker, Andrew Bergen, Wade Berrettini, Andreas Birgegård, Joseph Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Harry Brandt, Gerome BreenJulien Bryois, Katharina Buehren, Cynthia Bulik, Roland Burghardt, Matteo Cassina, Sven Cichon, Maurizio Clementi, Jonathan Coleman, Roger Cone, Philippe Courtet, Steven Crawford, Scott Crow, James Crowley, Unna Danner, Oliver Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece DeSocio, Danielle Dick, Dimitris Dikeos, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie 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 Foretova, Andreas Forstner, Monica Forzan, Christopher Franklin, Steven Gallinger, Héléna Gaspar, Ina Giegling, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Philip Gorwood, Monica Gratacos Mayora, Jakob Grove, Sébastien Guillaume, Yiran Guo, Hakon Hakonarson, Katherine Halmi, Ken Hanscombe, Konstantinos Hatzikotoulas, Joanna Hauser, Johannes Hebebrand, Sietske Helder, Anjali Henders, Stefan Herms, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Laura Huckins, James Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Susana Jiménez-Murcia, Craig Johnson, Jennifer Jordan, Antonio Julià, Anders Juréus, Gursharan Kalsi, Deborah Kaminská, Allan Kaplan, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien Kas, Walter Kaye, James Kennedy, Martin Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl Ri Kim, Katherine Kirk, Lars Klareskog, Kelly Klump, Gun Peggy Knudsen, Maria La Via, Mikael Landén, Janne Larsen, Stephanie Le Hellard, Virpi Leppä, Robert Levitan, Dong Li, Paul Lichtenstein, Lisa Lilenfeld, Bochao Danae Lin, Jolanta Lissowska, Jurjen Luykx, Pierre J. Magistretti, Mario Maj, Katrin Mannik, Sara Marsal, Christian Marshall, Nicholas Martin, Manuel Mattheisen, Morten Mattingsdal, Sara McDevitt, Peter McGuffin, Sarah Medland, Andres Metspalu, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Grant Montgomery, Preben Bo Mortensen, Melissa Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Claes Norring, Ioanna Ntalla, Catherine Olsen, Roel Ophoff, Julie O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John Pearson, Nancy Pedersen, Liselotte Petersen, Dalila Pinto, Kirstin Purves, Raquel Rabionet, Anu Raevuori, Nicolas Ramoz, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Stephan Ripke, Franziska Ritschel, Marion Roberts, Alessandro Rotondo, Dan Rujescu, Filip Rybakowski, Paolo Santonastaso, André Scherag, Stephen Scherer, Ulrike Schmidt, Nicholas Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita Slof-Op ‘t Landt, Agnieszka Slopien, Sandro Sorbi, Michael Strober, Garret Stuber, Patrick Sullivan, Beata Świątkowska, Jin Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Laura Thornton, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie van Elburg, Eric van Furth, Tracey Wade, Gudrun Wagner, Esther Walton, Hunna Watson, Thomas Werge, David Whiteman, Elisabeth Widen, D. Blake Woodside, Shuyang Yao, Zeynep Yilmaz, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Irene de Boer, Dorret I. Boomsma, Sigrid Børte, Daniel I. Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-Leon, George Davey-Smith, Martin Dichgans, Cornelia van Duijn, Tonu Esko, Ann Louise Esserlind, Michel Ferrari, Rune R. Frants, Tobias Freilinger, Nick Furlotte, Padhraig Gormley, Lyn Griffiths, Eija Hamalainen, Thomas Folkmann Hansen, Marjo Hiekkala, M. Arfan Ikram, Andres Ingason, Marjo Riitta Järvelin, Risto Kajanne, Mikko Kallela, Jaakko Kaprio, Mari Kaunisto, Lisette J.A. Kogelman, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimaki, Davor Lessel, Lannie Ligthart, Nadia Litterman, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Muller-Myhsok, Benjamin M. Neale, Carrie Northover, Dale R. Nyholt, Jes Olesen, Aarno Palotie, Priit Palta, Linda Pedersen, Nancy Pedersen, Danielle Posthuma, Patricia Pozo-Rosich, Alice Pressman, Olli Raitakari, Markus Schürks, Celia Sintas, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, David Strachan, Gisela Terwindt, Marta Vila-Pueyo, Maija Wessman, Bendik S. Winsvold, Huiying Zhao, John Anker Zwart, Michelle Agee, Babak Alipanahi, Adam Auton, Robert Bell, Katarzyna Bryc, Sarah Elson, Pierre Fontanillas, Nicholas Furlotte, Karl Heilbron, David Hinds, Karen Huber, Aaron Kleinman, Nadia Litterman, Jennifer McCreight, Matthew McIntyre, Joanna Mountain, Elizabeth Noblin, Carrie Northover, Steven Pitts, J. Sathirapongsasuti, Olga Sazonova, Janie Shelton, Suyash Shringarpure, Chao Tian, Joyce Tung, Vladimir Vacic, Catherine Wilson, Leo Brueggeman, Gerome Breen, Cynthia M. Bulik, Ernest Arenas, Jens Hjerling-Leffler, Patrick F. Sullivan

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.
Original languageEnglish (US)
Pages (from-to)482-493
Number of pages12
JournalNature Genetics
Volume52
Issue number5
DOIs
StatePublished - Apr 27 2020

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