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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, 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, 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, Leila Karhunen, Andreas Karwautz, Martien J. Kas, Walter H. Kaye, James L. Kennedy, Martin A. Kennedy, Anna Keski‐Rahkonen, Kirsty Kiezebrink, Youl‐Ri Kim, Katherine M. Kirk, Lars Klareskog, Kelly L. Klump, Gun Peggy Knudsen, Maria La Via, Mikael Landén, Janne Tidselbak Larsen, Stéphanie Le Hellard, Virpi Leppä, Robert D. Levitan, Dong Li, Paul Lichtenstein, Lisa Lilenfeld, Bochao Lin, Jolanta Lissowska, Jurjen J. Luykx, Pierre J. Magistretti, Mario Maj, Katrin Männik, Sara Marsal, Christian R. Marshall, Nicholas G. Martin, Manuel Mattheisen, Morten Mattingsdal, Sara McDevitt, Peter McGuffin, Sarah E. Medland, Andres Metspalu, Ingrid Meulenbelt, Nadia Micali, John C. Mitchell, Karen S. Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Grant W. Montgomery, Preben Bo Mortensen, Melissa A. Munn‐Chernoff, Benedetta Nacmias, Marie Navratilova, Claes Norring, Ιωάννα Ντάλλα, Catherine M. Olsen, Roel A. Ophoff, Julie O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papežová, Richard Parker, John F. Pearson, Nancy Pedersen, Liselotte Petersen, Dalila Pinto, Kirstin L. Purves, Raquel Rabionet, Anu Raevuori, Nicolás 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 W. Scherer, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Šlachtová, P. Eline Slagboom, M Landt, Agnieszka Slopien, Sandro Sorbi, Michael Strober, Garret D. Stuber, Patrick F. Sullivan, Beata Świątkowska, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Laura Thornton, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Άρτεμις Τσίτσικα, Marta Tyszkiewicz‐Nwafor, Konstantinos Tziouvas, Annemarie van Elburg, Eric F. van Furth, Tracey Wade, Gudrun Wagner, Esther Walton, Thomas Werge, David C. Whiteman, Elisabeth Widén, D. Blake Woodside, Shuyang Yao, Zeynep Yılmaz, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Verneri Anttila, Ville Artto, Andrea Carmine Belin, Irene de Boer, Sigrid Børte, Daniel I. Chasman, Lynn Cherkas, Anne Francke Christensen, Bru Cormand, Ester Cuenca-León, Martin Dichgans, Cornelia M. van Duijn, Tõnu Esko, Ann Louise Esserlind, Michel D. Ferrari, Rune R. Frants, Tobias Freilinger, Nick Furlotte, Padhraig Gormley, Lyn R. Griffiths, Eija Hämäläinen, Marjo Hiekkala, M. Arfan Ikram, Andrés Ingason, Marjo‐Riitta Järvelin, Risto Kajanne, Mikko Kallela, Mari Kaunisto, Christian Kubisch, Mitja Kurki, Tobias Kurth, Lenore Launer, Terho Lehtimäki, Davor Lessel, Lannie Ligthart, Arn van den Maagdenberg, Alfons Macaya, Rainer Malik, Massimo Mangino, George McMahon, Bertram Müller‐Myhsok, Benjamin M. Neale, Carrie A. M. Northover, Dale R. Nyholt, Jes Olesen, Priit Palta, Linda M. Pedersen, Daniëlle Posthuma, Patricia Pozo‐Rosich, Alice Pressman, Olli Raitakari, Markus Schürks, Cèlia Sintas, Kāri Stefánsson, Hreinn Stefánsson, Stacy Steinberg, David P. Strachan, Gisela M. Terwindt, Marta Vila‐Pueyo, Maija Wessman, Bendik S. Winsvold, Huiying Zhao, John‐Anker Zwart, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Karl Heilbron, David A. Hinds, Karen E. Huber, Aaron Kleinman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson, Leo Brueggeman, Cynthia M. Bulik, Ernest Arenas, Jens Hjerling‐Leffler
Bibliographic record
VenueNature Genetics · 2020
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsToronto General HospitalHospital for Sick ChildrenCentre for Addiction and Mental HealthUniversity of Toronto
FundersNational Institute of Mental HealthPerelman School of Medicine, University of PennsylvaniaUK Dementia Research InstituteNational Center of Neurology and PsychiatryBroad InstituteUniwersytet Medyczny im. Karola Marcinkowskiego w PoznaniuUniversität Duisburg-EssenRheinische Friedrich-Wilhelms-Universität BonnMedical Research CouncilTartu ÜlikoolRWTH Aachen UniversityCentre National de la Recherche ScientifiqueUniversitat de BarcelonaGöteborgs UniversitetCancerfondenUniversité Paris DescartesUniversitetet i OsloNational Institute of General Medical SciencesNational and Kapodistrian University of AthensKarolinska InstitutetLundbeckfondenHjärnfondenUniversità degli Studi di PadovaUniversité de MontpellierUniversity of PennsylvaniaTechnische Universität DresdenMedizinischen Hochschule HannoverUniversity of TorontoSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSahlgrenska AkademinH. Lundbeck A/SUniversity of BristolBundesministerium für Bildung und ForschungPfizerInstitut National de la Santé et de la Recherche MédicaleUniversitat Pompeu FabraAgence Nationale de la RechercheKommunfullmäktige, Stockholms StadAlzheimer's SocietyWellcome TrustUniversität BaselMassachusetts Institute of TechnologyEuropean CommissionUniversity of OtagoQIMR Berghofer Medical Research InstituteAarhus UniversitetHarokopio UniversityNational Science FoundationUniversity of MinnesotaVetenskapsrådetVirginia Commonwealth UniversityHarvard UniversityStiftelsen för Strategisk ForskningMichael J. Fox Foundation for Parkinson's Research
KeywordsBiologyParkinson's diseaseIdentification (biology)DiseaseGeneticsComplex diseaseEtiologyComputational biologyCell typeNeuroscienceCellBioinformaticsGeneInternal medicine
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.897
Threshold uncertainty score0.505
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.025
GPT teacher head0.283
Teacher spread0.259 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations387
Published2020
Admission routes2
Has abstractno