TY - JOUR
T1 - Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium
AU - International Headache Genetics Consortium
AU - 23andMe Research Team
AU - Bryois, Julien
AU - Skene, Nathan G.
AU - Hansen, Thomas Folkmann
AU - Kogelman, Lisette J.A.
AU - Watson, Hunna J.
AU - Liu, Zijing
AU - Adan, Roger
AU - Alfredsson, Lars
AU - Ando, Tetsuya
AU - Andreassen, Ole
AU - Baker, Jessica
AU - Bergen, Andrew
AU - Berrettini, Wade
AU - Birgegård, Andreas
AU - Boden, Joseph
AU - Boehm, Ilka
AU - Boni, Claudette
AU - Boraska Perica, Vesna
AU - Brandt, Harry
AU - Breen, Gerome
AU - Bryois, Julien
AU - Buehren, Katharina
AU - Bulik, Cynthia
AU - Burghardt, Roland
AU - Cassina, Matteo
AU - Cichon, Sven
AU - Clementi, Maurizio
AU - Coleman, Jonathan
AU - Cone, Roger
AU - Courtet, Philippe
AU - Crawford, Steven
AU - Crow, Scott
AU - Crowley, James
AU - Danner, Unna
AU - Davis, Oliver
AU - de Zwaan, Martina
AU - Dedoussis, George
AU - Degortes, Daniela
AU - DeSocio, Janiece
AU - Dick, Danielle
AU - Dikeos, Dimitris
AU - Dina, Christian
AU - Dmitrzak-Weglarz, Monika
AU - Docampo Martinez, Elisa
AU - Duncan, Laramie
AU - Egberts, Karin
AU - Ehrlich, Stefan
AU - Huckins, Laura
AU - Micali, Nadia
AU - Pinto, Dalila
N1 - Funding Information:
J.B. was funded by a grant from the Swiss National Science Foundation (P400PB_180792). N.G.S. was supported by the Wellcome Trust (108726/Z/15/Z). N.G.S. and L.B. performed part of the work at the Systems Genetics of Neurodegeneration summer school funded by BMBF as part of the e:Med programme (FKZ 01ZX1704). J.H.-L. was funded by the Swedish Research Council (Vetenskapsrådet, award 2014-3863), StratNeuro, the Wellcome Trust (108726/Z/15/Z) and the Swedish Brain Foundation (Hjärnfonden). P.F.S. was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501), the Horizon 2020 Program of the European Union (COSYN, RIA grant agreement no. 610307) and US NIMH (U01 MH109528 and R01 MH077139). E.A. was supported by the Swedish Research Council (VR 2016-01526), Swedish Foundation for Strategic Research (SLA SB16-0065), Karolinska Institutet (SFO Strat. Regen., Senior grant 2018), Cancerfonden (CAN 2016/572), Hjärnfonden (FO2017-0059) and Chen Zuckeberg Initiative: Neurodegeneration Challenge Network (2018-191929-5022). C.M.B. acknowledges funding from the Swedish Research Council (Vetenskapsrådet, award: 538-2013-8864) and the Klarman Family Foundation. This work is supported by the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. We thank the research participants from 23andMe and other cohorts for their contribution to this study.
Funding Information:
P.F.S. reports the following potentially competing financial interests: current—Lundbeck (advisory committee, grant recipient); past three years—Pfizer (scientific advisory board), Element Genomics (consultation fee) and Roche (speaker reimbursement). C.M.B. reports: Shire (grant recipient, Scientific Advisory Board member); Pearson and Walker (author, royalty recipient).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084195663&partnerID=8YFLogxK
U2 - 10.1038/s41588-020-0610-9
DO - 10.1038/s41588-020-0610-9
M3 - Article
C2 - 32341526
AN - SCOPUS:85084195663
SN - 1061-4036
VL - 52
SP - 482
EP - 493
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -