University of Oulu

Reynolds, R.H., Botía, J., Nalls, M.A. et al. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability. npj Parkinsons Dis. 5, 6 (2019). https://doi.org/10.1038/s41531-019-0076-6

Moving beyond neurons : the role of cell type-specific gene regulation in Parkinson’s disease heritability

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Author: Reynolds, Regina H.1; Botia, Juan1,2; Nalls, Mike A.3,4;
Hardy, John1,5; Taliun, Sarah A. Gagliano6,7; Ryten, Mina1; Noyce, Alastair J.1,8; Nicolas, Aude3; Cookson, Mark R.3; Bandres-Ciga, Sara3; Gibbs, J. Raphael3; Hernandez, Dena G.3; Singleton, Andrew B.3; Reed, Xylena3; Leonard, Hampton3; Blauwendraat, Cornelis3,9; Faghri, Faraz3,10; Bras, Jose5,11; Guerreiro, Rita5,11; Tucci, Arianna11; Kia, Demis A.11; Houlden, Henry11; Plun-Favreau, Helene11; Mok, Kin Y.11; Wood, Nicholas W.11; Lovering, Ruth11; R'Bibo, Lea11; Rizig, Mie11; Chelban, Viorica11; Trabzuni, Daniah11,12; Tan, Manuela13; Morris, Huw R.13; Middlehurst, Ben14; Quinn, John14; Billingsley, Kimberley14; Holmans, Peter15; Kinghorn, Kerri J.16; Lewis, Patrick17; Escott-Price, Valentina18; Williams, Nigel18; Foltynie, Thomas19; Brice, Alexis20; Danjou, Fabrice20; Lesage, Suzanne20; Corvol, Jean-Christophe20; Martinez, Maria20,21; Giri, Anamika22,23; Schulte, Claudia22,23; Brockmann, Kathrin22,23; Simon-Sanchez, Javier22,23; Heutink, Peter22,23; Gasser, Thomas22,23; Rizzu, Patrizia23; Sharma, Manu24; Shulman, Joshua M.25,26,27,28; Robak, Laurie25,26,27; Lubbe, Steven29; Mencacci, Niccolo E.30; Finkbeiner, Steven31,32,33; Lungu, Codrin34; Scholz, Sonja W.35; Gan-Or, Ziv36,37; Rouleau, Guy A.36,37; Krohan, Lynne38; van Hilten, Jacobus J.39; Marinus, Johan39; Adarmes-Gomez, Astrid D.40; Bernal-Bernal, Inmaculada40; Bonilla-Toribio, Marta40; Buiza-Rueda, Dolores40; Carrillo, Fatima40; Carrion-Claro, Mario40; Mir, Pablo40; Gomez-Garre, Pilar40; Jesus, Silvia40; Labrador-Espinosa, Miguel A.40; Macias, Daniel40; Vargas-Gonzalez, Laura40; Mendez-del-Barrio, Carlota40; Perinan-Tocino, Teresa40; Tejera-Parrado, Cristina40; Diez-Fairen, Monica41,42; Aguilar, Miquel41,42; Alvarez, Ignacio41,42; Teresa Boungiorno, Mara41,42; Carcel, Maria41,42; Pastor, Pau41,42; Pablo Tartari, Juan41,42; Alvarez, Victoria43; Menendez Gonzalez, Manuel43; Blazquez, Marta43; Garcia, Ciara43; Suarez-Sanmartin, Esther43; Javier Barrero, Francisco44; Mondragon Rezola, Elisabet45; Bergareche Yarza, Jesus Alberto45; Gorostidi Pagola, Ana45; de Munain Arregui, Adolfo Lopez45; Ruiz-Martinez, Javier45; Cerdan, Debora46; Duarte, Jacinto46; Clarimon, Jordi47,48; Dols-Icardo, Oriol47,48; Infante, Jon48,49,50; Marin, Juan48,51; Kulisevsky, Jaime48,51; Pagonabarraga, Javier48,51; Gonzalez-Aramburu, Isabel49; Sanchez Rodriguez, Antonio49; Sierra, Mara49; Duran, Raquel52; Ruz, Clara52; Vives, Francisco52; Escamilla-Sevilla, Francisco53; Minguez, Adolfo53; Camara, Ana54; Compta, Yaroslau54; Ezquerra, Mario54; Jose Marti, Maria54; Fernandez, Manel54; Munoz, Esteban54; Fernandez-Santiago, Ruben54; Tolosa, Eduard54; Valldeoriola, Francesc54; Garcia-Ruiz, Pedro55; Gomez Heredia, Maria Jose56; Perez Errazquin, Francisco56; Hoenicka, Janet57; Jimenez-Escrig, Adriano58; Carlos Martinez-Castrillo, Juan58; Luis Lopez-Sendon, Jose58; Martinez Torres, Irene59; Tabernero, Cesar46; Vela, Lydia60; Zimprich, Alexander61; Pihlstrom, Lasse62; Koks, Sulev63,64,65; Taba, Pille66,67; Majamaa, Kari68,69,70; Siitonen, Ari68,69,70; Okubadejo, Njideka U.71; Ojo, Oluwadamilola O.71; Pitcher, Toni72,73; Anderson, Tim72,73; Bentley, Steven74; Fowdar, Javed74; Mellick, George74; Dalrymple-Alford, John75; Henders, Anjali K.76; Kassam, Irfahan76; Montgomery, Grant76; Sidorenko, Julia76; Zhang, Futao76; Xue, Angli76; Vallerga, Costanza L.76; Wallace, Leanne76; Wray, Naomi R.76,77; Yang, Jian76,77; Visscher, Peter M.76,77; Gratten, Jacob76,77; Silburn, Peter A.77; Halliday, Glenda78; Hickie, Ian78; Kwok, John78; Lewis, Simon78; Kennedy, Martin79; Pearson, John79
Organizations: 1UCL, Dept Neurodegenerat Dis, Inst Neurol, London, England.
2Univ Murcia, Dept Ingn Informat & Comunicac, Murcia, Spain.
3NIH, Lab Neurogenet, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA.
4Data Tecn Int, Glen Echo, MD USA.
5UCL, UK Dementia Res Inst, London, England.
6Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
7Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
8QMUL, Wolfson Inst Prevent Med, Prevent Neurol Unit, London, England.
9NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
10Univ Illinois, Dept Comp Sci, Urbana, IL USA.
11UCL, Dept Mol Neurosci, London, England.
12King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 1121, Saudi Arabia.
13UCL, Dept Clin Neurosci, London, England.
14Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
15MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales.
16UCL, Inst Hlth Ageing, London, England.
17Univ Reading, Reading, Berks, England.
18Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales.
19UCL Inst Neurol, London, England.
20UPMC Univ Paris 06, Sorbonne Univ, AP HP,ICM,Inserm U 1127,CNRS,UMR 7225, Pitie Salpetriere Hosp,Inst Cerveau & Moelle Epin, Paris, France.
21Paul Sabatier Univ, Toulouse, France.
22Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany.
23German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany.
24Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Ctr Genet Epidemiol, Tubingen, Germany.
25Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA.
26Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA.
27Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
28Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA.
29Northwestern Univ, Ken & Ruth Davee Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA.
30Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA.
31Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA.
32Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA.
33Taube Koret Ctr Neurodegenerat Dis Res, Gladstone Inst Neurol Dis, San Francisco, CA USA.
34NINDS, NIH, Div Clin Res, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
35NINDS, Neurodegenerat Dis Res Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.
36McGill Univ, Dept Human Genet, Montreal Neurol Inst & Hosp, Dept Neurol, Montreal, PQ H3A 0G4, Canada.
37McGill Univ, Dept Human Genet, Montreal Neurol Inst & Hosp, Dept Neurosurg, Montreal, PQ H3A 0G4, Canada.
38McGill Univ, Dept Human Genet, Montreal, PQ H3A 0G4, Canada.
39Leiden Univ, Dept Neurol, Med Ctr, Leiden, Netherlands.
40Univ Seville, CSIC, Hosp Univ Virgen Rocio, Inst Biomed Sevilla IBiS, Seville, Spain.
41Univ Hosp Mutua Terrassa, Dept Neurol, Fundacio Docencia & Recerca Mutua Terrassa, Barcelona, Spain.
42Univ Hosp Mutua Terrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain.
43Hosp Univ Cent Asturias, Oviedo, Spain.
44Hosp Univ Parque Tecnol Salud, Granada, Spain.
45Inst Invest Sanitaria Biodonostia, San Sebastian, Spain.
46Hosp Gen Segovia, Segovia, Spain.
47Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Memory Unit,Dept Neurol, Barcelona, Spain.
48Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain.
49Hosp Univ Marques Valdecilla, IDIVAL, Santander, Spain.
50Univ Cantabria, Santander, Spain.
51Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Movement Disorders Unit,Dept Neurol, Barcelona, Spain.
52Univ Granada, Ctr Invest Biomed, Granada, Spain.
53Hosp Univ Virgen Nieves, Inst Invest Biosanitaria Granada, Granada, Spain.
54Hosp Clin Barcelona, Barcelona, Spain.
55Inst Invest Sanitaria Fdn Jimenez Diaz, Madrid, Spain.
56Hosp Univ Virgen Victoria, Malaga, Spain.
57Inst Recerca St Joan Deu, Barcelona, Spain.
58Hosp Univ Ramon & Cajal, Madrid, Spain.
59Hosp Univ & Politecn La Fe, Inst Invest Sanitaria La Fe, Dept Neurol, Valencia, Spain.
60Hosp Univ Fdn Alcorcon, Dept Neurol, Madrid, Spain.
61Med Univ Vienna, Dept Neurol, Vienna, Austria.
62Oslo Univ Hosp, Dept Neurol, Oslo, Norway.
63Univ Tartu, Dept Pathophysiol, Tartu, Estonia.
64Estonian Univ Life Sci, Dept Reprod Biol, Tartu, Estonia.
65Perron Inst Neurol & Translat Sci, Perth, WA, Australia.
66Univ Tartu, Dept Neurol, Tartu, Estonia.
67Univ Tartu, Dept Neurosurg, Tartu, Estonia.
68Univ Oulu, Dept Neurol, Inst Clin Med, Oulu, Finland.
69Oulu Univ Hosp, Dept Neurol, Oulu, Finland.
70Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.
71Univ Lagos, Lagos, Lagos State, Nigeria.
72New Zealand Brain Res Inst, Christchurch, New Zealand.
73Univ Otago, Dept Med, Christchurch, New Zealand.
74Griffith Univ, Griffith Inst Drug Discovery, Brisbane, Qld, Australia.
75Univ Canterbury, New Zealand Brain Res Inst, Dept Psychol, Christchurch, New Zealand.
76Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.
77Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.
78Univ Sydney, Sydney Med Sch, Brain & Mind Ctr, Sydney, NSW, Australia.
79Univ Otago, Dept Pathol, Christchurch, New Zealand.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.8 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202003117846
Language: English
Published: Springer Nature, 2019
Publish Date: 2020-03-11
Description:

Abstract

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

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Series: npj Parkinson's disease
ISSN: 2373-8057
ISSN-E: 2373-8057
ISSN-L: 2373-8057
Volume: 5
Article number: 6
DOI: 10.1038/s41531-019-0076-6
OADOI: https://oadoi.org/10.1038/s41531-019-0076-6
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3111 Biomedicine
3112 Neurosciences
Subjects:
Funding: R.H.R. was supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration. M.A.N. was supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA. J.H. and M.R. were supported by the UK Medical Research Council (MRC), with J.H. supported by a grant (MR/N026004/) and M.R. through the award of a Tenure-track Clinician Scientist Fellowship (MR/N008324/1). J.H. was also supported by the UK Dementia Research Institute. Full consortia acknowledgements are available in the supplemental materials (Text S2).
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