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; Eating Disorders Working Group of the Psychiatric Genomics Consortium; International Headache Genetics Consortium; 23andMe Research Team; Leo Brueggeman; Gerome Breen; Cynthia Bulik; Ernest Arenas; Jens Hjerling-Leffler; Patrick F. Sullivan

doi:10.1038/s41588-020-0610-9

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, Eating Disorders Working Group of the Psychiatric Genomics Consortium, International Headache Genetics Consortium, 23andMe Research Team, Leo Brueggeman, Gerome Breen, Cynthia Bulik, Ernest Arenas, Jens Hjerling-Leffler^* (Corresponding Author), Patrick F. Sullivan^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

150 Citations (Scopus)

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 language	English
Pages (from-to)	482-493
Number of pages	12
Journal	Nature Genetics
Volume	52
Early online date	27 Apr 2020
DOIs	https://doi.org/10.1038/s41588-020-0610-9
Publication status	Published - 1 May 2020

Bibliographical note

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.

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.

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Bryois, J., Skene, N. G., Hansen, T. F., Kogelman, L. J. A., Watson, H. J., Liu, Z., Eating Disorders Working Group of the Psychiatric Genomics Consortium, International Headache Genetics Consortium, 23andMe Research Team, Brueggeman, L., Breen, G., Bulik, C., Arenas, E., Hjerling-Leffler, J., & Sullivan, P. F. (2020). Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease. Nature Genetics, 52, 482-493. https://doi.org/10.1038/s41588-020-0610-9

Bryois, J, Skene, NG, Hansen, TF, Kogelman, LJA, Watson, HJ, Liu, Z, Eating Disorders Working Group of the Psychiatric Genomics Consortium, International Headache Genetics Consortium, 23andMe Research Team, Brueggeman, L, Breen, G, Bulik, C, Arenas, E, Hjerling-Leffler, J & Sullivan, PF 2020, 'Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease', Nature Genetics, vol. 52, pp. 482-493. https://doi.org/10.1038/s41588-020-0610-9

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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{\textquoteright}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{\textquoteright}s disease.",

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note = "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 (Vetenskapsr{\aa}det, award 2014-3863), StratNeuro, the Wellcome Trust (108726/Z/15/Z) and the Swedish Brain Foundation (Hj{\"a}rnfonden). P.F.S. was supported by the Swedish Research Council (Vetenskapsr{\aa}det, 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), Hj{\"a}rnfonden (FO2017-0059) and Chen Zuckeberg Initiative: Neurodegeneration Challenge Network (2018-191929-5022). C.M.B. acknowledges funding from the Swedish Research Council (Vetenskapsr{\aa}det, 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{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK. We thank the research participants from 23andMe and other cohorts for their contribution to this study. 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: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Watson, Hunna J.

AU - Liu, Zijing

AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium

AU - International Headache Genetics Consortium

AU - 23andMe Research Team

AU - Brueggeman, Leo

AU - Breen, Gerome

AU - Bulik, Cynthia

AU - Arenas, Ernest

AU - Hjerling-Leffler, Jens

AU - Sullivan, Patrick F.

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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.

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

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