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5 results on '"Krohan L."'

1. Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Author

Guelfi S., D’Sa K., Botía J.A., Vandrovcova J., Reynolds R.H., Zhang D., Trabzuni D., Collado-Torres L., Thomason A., Quijada Leyton P., Gagliano Taliun S.A., Nalls M.A., Noyce A.J., Nicolas A., Cookson M.R., Bandres-Ciga S., Gibbs J.R., Hernandez D.G., Singleton A.B., Reed X., Leonard H., Blauwendraat C., Faghri F., Bras J., Guerreiro R., Tucci A., Kia D.A., Houlden H., Plun-Favreau H., Mok K.Y., Wood N.W., Lovering R., R’Bibo L., Rizig M., Chelban V., Tan M., Morris H.R., Middlehurst B., Quinn J., Billingsley K., Holmans P., Kinghorn K.J., Lewis P., Escott-Price V., Williams N., Foltynie T., Brice A., Danjou F., Lesage S., Corvol J.-C., Martinez M., Giri A., Schulte C., Brockmann K., Simón-Sánchez J., Heutink P., Gasser T., Rizzu P., Sharma M., Shulman J.M., Robak L., Lubbe S., Mencacci N.E., Finkbeiner S., Lungu C., Scholz S.W., Gan-Or Z., Rouleau G.A., Krohan L., van Hilten J.J., Marinus J., Adarmes-Gómez A.D., Bernal-Bernal I., Bonilla-Toribio M., Buiza-Rueda D., Carrillo F., Carrión-Claro M., Mir P., Gómez-Garre P., Jesús S., Labrador-Espinosa M.A., Macias D., Vargas-González L., Méndez-del-Barrio C., Periñán-Tocino T., Tejera-Parrado C., Diez-Fairen M., Aguilar M., Alvarez I., Boungiorno M.T., Carcel M., Pastor P., Tartari J.P., Alvarez V., González M.M., Blazquez M., Garcia C., Suarez-Sanmartin E., Barrero F.J., Rezola E.M., Yarza J.A.B., Pagola A.G., Arregui A.L.M., Ruiz-Martínez J., Cerdan D., Duarte J., Clarimón J., Dols-Icardo O., Infante J., Marín J., Kulisevsky J., Pagonabarraga J., Gonzalez-Aramburu I., Rodriguez A.S., Sierra M., Duran R., Ruz C., Vives F., Escamilla-Sevilla F., Mínguez A., Cámara A., Compta Y., Ezquerra M., Marti M.J., Fernández M., Muñoz E., Fernández-Santiago R., Tolosa E., Valldeoriola F., García-Ruiz P., Heredia M.J.G., Errazquin F.P., Hoenicka J., Jimenez-Escrig A., Martínez-Castrillo J.C., Lopez-Sendon J.L., Torres I.M., Tabernero C., Vela L., Zimprich A., Pihlstrom L., Koks S., Taba P., Majamaa K., Siitonen A., Okubadejo N.U., Ojo O.O., Forabosco P., Walker R., Small K.S., Smith C., Ramasamy A., Hardy J., Weale M.E., and Ryten M.

Subjects
medicine, RNA splicing, phenotype, brain, genotype, Quantitative Trait Loci, genetic analysis, Polymorphism, Single Nucleotide, Article, genetic regulation, mental disease, transcriptomics, quantitative trait locus, expression quantitative trait locus, single nucleotide polymorphism, Humans, genetics, human, reproducibility, Alleles, Neurons, genome-wide association study, human cell, allele, Putamen, Reproducibility of Results, RNA sequencing, Parkinson Disease, gene expression regulation, cell, cohort analysis, neurologic disease, human tissue, schizophrenia, Substantia Nigra, disease incidence, physiology, gene expression, RNA, physiological response, Nervous System Diseases, nerve cell, Transcriptome, nervous system disorder, basal ganglion
Abstract

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/. © 2020, The Author(s).

Published
2020

2. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Author

Billingsley, Kimberley J, Barbosa, Ines A, Bandres-Ciga, Sara, Quinn, John P, Bubb, Vivien J, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A, Blauwendraat, Cornelis, Gan-Or, Ziv, Gibbs, J Raphael, Nalls, Mike A, Singleton, Andrew, Ryten, Mina, Koks, Sulev, Noyce, A, Tucci, A, Middlehurst, B, Kia, D, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Mok, K, Kinghorn, K, Wood, N, Lewis, P, Guerreiro, R, Loverin, R, R'Bibo, L, Rizig, M, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Brice, A, Danjou, F, Lesage, S, Martinez, M, Giri, A, Schulte, C, Brockmann, K, Simon-Sanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, M, Faghri, F, Hernandez, D, Shulman, J, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, N, Lungu, C, Scholz, S, Reed, X, Leonard, H, Rouleau, G, Krohan, L, van Hilten, J, Marinus, J, Adarmes-Gomez, A, Aguilar, M, Alvarez, I, Alvarez, V, Javier Barrero, F, Bergareche Yarza, J, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio Bernal, M, Boungiorne, M, Buiza-Rueda, Dolores, Camara, A, Carcel, M, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, RI, Escamilla-Sevilla, F, Ezquerra, M, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Gomez Heredia, M, Gonzalez-Aramburu, I, Gorostidi Pagola, A, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, M, Lopez-Sendon, J, de Munain Arregui, A Lopez, Macias, D, Martinez Torres, I, Marin, J, Jose Marti, M, Martinez-Castrillo, J, Mendez-del-Barrio, C, Menendez Gonzalez, M, Minguez, A, Mir, P, Mondragon Rezola, E, Munoz, E, Pagonabarraga, J, Pastor, P, Perez Errazquin, F, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Sanchez Rodriguez, A, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Pablo Tartari, J, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Taba, P, Majamaa, K, Siitonen, A, Okubadejo, N, Ojo, O, IPDGC, and Universidad de Cantabria

Subjects
0301 basic medicine, Mitochondrial DNA, medicine.medical_specialty, Aging, Parkinson's disease, Mitochondrial disease, Mitochondrion, Biology, Neurodegenerative, Bioinformatics, lcsh:RC346-429, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Mendelian randomization, Mitophagy, medicine, Genetics, 2.1 Biological and endogenous factors, Aetiology, lcsh:Neurology. Diseases of the nervous system, Parkinson's Disease, Medical genetics, Neurosciences, medicine.disease, Brain Disorders, International Parkinson’s Disease Genomics Consortium, 030104 developmental biology, Proteostasis, Neurology, Risk factors, Neurological, Neurology (clinical), Medical genetic, 030217 neurology & neurosurgery
Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949

Published
2019

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

Author

Reynolds, R.H., Botia, J., Nalls, M.A., Hardy, J., Taliun, S.A.G., Ryten, M., Noyce, A.J., Nicolas, A., Cookson, M.R., Bandres-Ciga, S., Gibbs, J.R., Hernandez, D.G., Singleton, A.B., Reed, X., Leonard, H., Blauwendraat, C., Faghri, F., Bras, J., Guerreiro, R., Tucci, A., Kia, D.A., Houlden, H., Plun-Favreau, H., Mok, K.Y., Wood, N.W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, V., Trabzuni, D., Tan, M., Morris, H.R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, P., Kinghorn, K.J., Lewis, P., Escott-Price, V., Williams, N., Foltynie, T., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simon-Sanchez, J., Heutink, P., Gasser, T., Rizzu, P., Sharma, M., Shulman, J.M., Robak, L., Lubbe, S., Mencacci, N.E., Finkbeiner, S., Lungu, C., Scholz, S.W., Gan-Or, Z., Rouleau, G.A., Krohan, L., Hilten, J.J. van, Marinus, J., Adarmes-Gomez, A.D., Bernal-Bernal, I., Bonilla-Toribio, M., Buiza-Rueda, D., Carrillo, F., Carrion-Claro, M., Mir, P., Gomez-Garre, P., Jesus, S., Labrador-Espinosa, M.A., Macias, D., Vargas-Gonzalez, L., Mendez-del-Barrio, C., Perinan-Tocino, T., Tejera-Parrado, C., Diez-Fairen, M., Aguilar, M., Alvarez, I., Boungiorno, M.T., Carcel, M., Pastor, P., Tartari, J.P., Alvarez, V., Gonzalez, M.M., Blazquez, M., Garcia, C., Suarez-Sanmartin, E., Barrero, F.J., Rezola, E.M., Yarza, J.A.B., Pagola, A.G., Arregui, A.L.D., Ruiz-Martinez, J., Cerdan, D., Duarte, J., Clarimon, J., Dols-Icardo, O., Infante, J., Marin, J., Kulisevsky, J., Pagonabarraga, J., Gonzalez-Aramburu, I., Rodriguez, A.S., Sierra, M., Duran, R., Ruz, C., Vives, F., Escamilla-Sevilla, F., Minguez, A., Camara, A., Compta, Y., Ezquerra, M., Marti, M.J., Fernandez, M., Munoz, E., Fernandez-Santiago, R., Tolosa, E., Valldeoriola, F., Garcia-Ruiz, P., Heredia, M.J.G., Errazquin, F.P., Hoenicka, J., Jimenez-Escrig, A., Martinez-Castrillo, J.C., Lopez-Sendon, J.L., Torres, I.M., Tabernero, C., Vela, L., Zimprich, A., Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N.U., Ojo, O.O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, A.K., Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F.T., Xue, A.L., Vallerga, C.L., Wallace, L., Wray, N.R., Yang, J., Visscher, P.M., Gratten, J., Silburn, P.A., Halliday, G., Hickie, I., Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Int Parkinsons Dis Genomics, and Syst Genomics Parkinsons Dis

Published
2019

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

Author

Reynolds, R. H., Botía, J., Nalls, M. A., Noyce, A. J., Nicolas, A., Cookson, M. R., Bandres-Ciga, S., Gibbs, J. R., Hernandez, D. G., Singleton, A. B., Reed, X., Leonard, H., Blauwendraat, Cornelis, Faghri, F., Bras, J., Guerreiro, Rita, Tucci, A., Kia, Demis A, Houlden, Henry, Plun-Favreau, H., Mok, K. Y., Wood, N. W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, Viorica, Trabzuni, D., Tan, M., Morris, H. R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, Peter, Kinghorn, K. J., Lewis, P., Escott-Price, Valentina, Williams, N., Foltynie, T., Brice, Alexis, Danjou, F., Lesage, S., Corvol, Jean-Christophe, Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, Peter, Gasser, Thomas, Rizzu, P., Sharma, M., Shulman, J. M., Robak, L., Lubbe, S., Mencacci, N. E., Finkbeiner, S., Lungu, C., Scholz, S. W., Gan-Or, Z., Rouleau, G. A., Krohan, L., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A.D, Bernal-Bernal, I., Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Carrillo, F., Carrión-Claro, M., Mir, P., Gómez-Garre, P., Jesús, S., Labrador-Espinosa, Miguel A, Macías-García, Daniel, Vargas-González, L., Méndez-del-Barrio, C., Periñán-Tocino, T., Tejera-Parrado, C., Diez-Fairen, Monica., Aguilar Barberà, Miquel, Alvarez, Ignacio, Boungiorno, M. T., Carcel, M., Pastor, Pau, Tartari, J. P., Alvarez, V., González, M. M., Blázquez Estrada, Marta, Garcia, C.., Suarez-Sanmartin, E., Barrero, F. J., Rezola, E. M., Yarza, J. A. B., Pagola, A. G., de Munain Arregui, A. L., Ruiz-Martínez, J., Cerdan, Debora, Duarte, J., Clarimón, Jordi, Dols Icardo, Oriol, Infante, J., Marín, J., Kulisevsky, Jaime, Pagonabarraga Mora, Javier, Gonzalez-Aramburu, Isabel, Rodriguez, A. S., Sierra, M., Duran, Raquel, Ruz, C., Vives, F., Escamilla-Sevilla, F., Mínguez, A., Cámara, Ana, Compta, Yaroslau, Ezquerra, M., Marti, M. J., Fernández, M., Muñoz García, José Esteban, Fernández Santiago, Rubén, Tolosa, E., Valldeoriola, F., García-Ruiz, P., Heredia, M. J. G., Errazquin, F. P., Hoenicka, J., Jimenez-Escrig, A., Martínez-Castrillo, J. C., Lopez-Sendon, J. L., Torres, I. M., Tabernero, C., Vela, Lydia, Zimprich, Alexander, Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N. U., Ojo, O. O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, Anjali K, Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F., Xue, A., Vallerga, C. L., Wallace, Leanne, Wray, N. R., Yang, J., Visscher, P. M., Gratten, J., Silburn, P. A., Halliday, G., Hickie, Ian B, Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Hardy, J., Gagliano Taliun, S. A., Ryten, Mina, and Universitat Autònoma de Barcelona

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.

Published
2019

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

Author

Reynolds, R. H. (Regina H.), Botia, J. (Juan), Nalls, M. A. (Mike A.), Hardy, J. (John), Taliun, S. A. (Sarah A. Gagliano), Ryten, M. (Mina), Noyce, A. J. (Alastair J.), Nicolas, A. (Aude), Cookson, M. R. (Mark R.), Bandres-Ciga, S. (Sara), Gibbs, J. R. (J. Raphael), Hernandez, D. G. (Dena G.), Singleton, A. B. (Andrew B.), Reed, X. (Xylena), Leonard, H. (Hampton), Blauwendraat, C. (Cornelis), Faghri, F. (Faraz), Bras, J. (Jose), Guerreiro, R. (Rita), Tucci, A. (Arianna), Kia, D. A. (Demis A.), Houlden, H. (Henry), Plun-Favreau, H. (Helene), Mok, K. Y. (Kin Y.), Wood, N. W. (Nicholas W.), Lovering, R. (Ruth), R'Bibo, L. (Lea), Rizig, M. (Mie), Chelban, V. (Viorica), Trabzuni, D. (Daniah), Tan, M. (Manuela), Morris, H. R. (Huw R.), Middlehurst, B. (Ben), Quinn, J. (John), Billingsley, K. (Kimberley), Holmans, P. (Peter), Kinghorn, K. J. (Kerri J.), Lewis, P. (Patrick), Escott-Price, V. (Valentina), Williams, N. (Nigel), Foltynie, T. (Thomas), Brice, A. (Alexis), Danjou, F. (Fabrice), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Martinez, M. (Maria), Giri, A. (Anamika), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Simon-Sanchez, J. (Javier), Heutink, P. (Peter), Gasser, T. (Thomas), Rizzu, P. (Patrizia), Sharma, M. (Manu), Shulman, J. M. (Joshua M.), Robak, L. (Laurie), Lubbe, S. (Steven), Mencacci, N. E. (Niccolo E.), Finkbeiner, S. (Steven), Lungu, C. (Codrin), Scholz, S. W. (Sonja W.), Gan-Or, Z. (Ziv), Rouleau, G. A. (Guy A.), Krohan, L. (Lynne), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Adarmes-Gomez, A. D. (Astrid D.), Bernal-Bernal, I. (Inmaculada), Bonilla-Toribio, M. (Marta), Buiza-Rueda, D. (Dolores), Carrillo, F. (Fatima), Carrion-Claro, M. (Mario), Mir, P. (Pablo), Gomez-Garre, P. (Pilar), Jesus, S. (Silvia), Labrador-Espinosa, M. A. (Miguel A.), Macias, D. (Daniel), Vargas-Gonzalez, L. (Laura), Mendez-del-Barrio, C. (Carlota), Perinan-Tocino, T. (Teresa), Tejera-Parrado, C. (Cristina), Diez-Fairen, M. (Monica), Aguilar, M. (Miquel), Alvarez, I. (Ignacio), Teresa Boungiorno, M. (Mara), Carcel, M. (Maria), Pastor, P. (Pau), Pablo Tartari, J. (Juan), Alvarez, V. (Victoria), Menendez Gonzalez, M. (Manuel), Blazquez, M. (Marta), Garcia, C. (Ciara), Suarez-Sanmartin, E. (Esther), Javier Barrero, F. (Francisco), Mondragon Rezola, E. (Elisabet), Bergareche Yarza, J. A. (Jesus Alberto), Gorostidi Pagola, A. (Ana), de Munain Arregui, A. L. (Adolfo Lopez), Ruiz-Martinez, J. (Javier), Cerdan, D. (Debora), Duarte, J. (Jacinto), Clarimon, J. (Jordi), Dols-Icardo, O. (Oriol), Infante, J. (Jon), Marin, J. (Juan), Kulisevsky, J. (Jaime), Pagonabarraga, J. (Javier), Gonzalez-Aramburu, I. (Isabel), Sanchez Rodriguez, A. (Antonio), Sierra, M. (Mara), Duran, R. (Raquel), Ruz, C. (Clara), Vives, F. (Francisco), Escamilla-Sevilla, F. (Francisco), Minguez, A. (Adolfo), Camara, A. (Ana), Compta, Y. (Yaroslau), Ezquerra, M. (Mario), Jose Marti, M. (Maria), Fernandez, M. (Manel), Munoz, E. (Esteban), Fernandez-Santiago, R. (Ruben), Tolosa, E. (Eduard), Valldeoriola, F. (Francesc), Garcia-Ruiz, P. (Pedro), Gomez Heredia, M. J. (Maria Jose), Perez Errazquin, F. (Francisco), Hoenicka, J. (Janet), Jimenez-Escrig, A. (Adriano), Carlos Martinez-Castrillo, J. (Juan), Luis Lopez-Sendon, J. (Jose), Martinez Torres, I. (Irene), Tabernero, C. (Cesar), Vela, L. (Lydia), Zimprich, A. (Alexander), Pihlstrom, L. (Lasse), Koks, S. (Sulev), Taba, P. (Pille), Majamaa, K. (Kari), Siitonen, A. (Ari), Okubadejo, N. U. (Njideka U.), Ojo, O. O. (Oluwadamilola O.), Pitcher, T. (Toni), Anderson, T. (Tim), Bentley, S. (Steven), Fowdar, J. (Javed), Mellick, G. (George), Dalrymple-Alford, J. (John), Henders, A. K. (Anjali K.), Kassam, I. (Irfahan), Montgomery, G. (Grant), Sidorenko, J. (Julia), Zhang, F. (Futao), Xue, A. (Angli), Vallerga, C. L. (Costanza L.), Wallace, L. (Leanne), Wray, N. R. (Naomi R.), Yang, J. (Jian), Visscher, P. M. (Peter M.), Gratten, J. (Jacob), Silburn, P. A. (Peter A.), Halliday, G. (Glenda), Hickie, I. (Ian), Kwok, J. (John), Lewis, S. (Simon), Kennedy, M. (Martin), Pearson, J. (John), Reynolds, R. H. (Regina H.), Botia, J. (Juan), Nalls, M. A. (Mike A.), Hardy, J. (John), Taliun, S. A. (Sarah A. Gagliano), Ryten, M. (Mina), Noyce, A. J. (Alastair J.), Nicolas, A. (Aude), Cookson, M. R. (Mark R.), Bandres-Ciga, S. (Sara), Gibbs, J. R. (J. Raphael), Hernandez, D. G. (Dena G.), Singleton, A. B. (Andrew B.), Reed, X. (Xylena), Leonard, H. (Hampton), Blauwendraat, C. (Cornelis), Faghri, F. (Faraz), Bras, J. (Jose), Guerreiro, R. (Rita), Tucci, A. (Arianna), Kia, D. A. (Demis A.), Houlden, H. (Henry), Plun-Favreau, H. (Helene), Mok, K. Y. (Kin Y.), Wood, N. W. (Nicholas W.), Lovering, R. (Ruth), R'Bibo, L. (Lea), Rizig, M. (Mie), Chelban, V. (Viorica), Trabzuni, D. (Daniah), Tan, M. (Manuela), Morris, H. R. (Huw R.), Middlehurst, B. (Ben), Quinn, J. (John), Billingsley, K. (Kimberley), Holmans, P. (Peter), Kinghorn, K. J. (Kerri J.), Lewis, P. (Patrick), Escott-Price, V. (Valentina), Williams, N. (Nigel), Foltynie, T. (Thomas), Brice, A. (Alexis), Danjou, F. (Fabrice), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Martinez, M. (Maria), Giri, A. (Anamika), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Simon-Sanchez, J. (Javier), Heutink, P. (Peter), Gasser, T. (Thomas), Rizzu, P. (Patrizia), Sharma, M. (Manu), Shulman, J. M. (Joshua M.), Robak, L. (Laurie), Lubbe, S. (Steven), Mencacci, N. E. (Niccolo E.), Finkbeiner, S. (Steven), Lungu, C. (Codrin), Scholz, S. W. (Sonja W.), Gan-Or, Z. (Ziv), Rouleau, G. A. (Guy A.), Krohan, L. (Lynne), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Adarmes-Gomez, A. D. (Astrid D.), Bernal-Bernal, I. (Inmaculada), Bonilla-Toribio, M. (Marta), Buiza-Rueda, D. (Dolores), Carrillo, F. (Fatima), Carrion-Claro, M. (Mario), Mir, P. (Pablo), Gomez-Garre, P. (Pilar), Jesus, S. (Silvia), Labrador-Espinosa, M. A. (Miguel A.), Macias, D. (Daniel), Vargas-Gonzalez, L. (Laura), Mendez-del-Barrio, C. (Carlota), Perinan-Tocino, T. (Teresa), Tejera-Parrado, C. (Cristina), Diez-Fairen, M. (Monica), Aguilar, M. (Miquel), Alvarez, I. (Ignacio), Teresa Boungiorno, M. (Mara), Carcel, M. (Maria), Pastor, P. (Pau), Pablo Tartari, J. (Juan), Alvarez, V. (Victoria), Menendez Gonzalez, M. (Manuel), Blazquez, M. (Marta), Garcia, C. (Ciara), Suarez-Sanmartin, E. (Esther), Javier Barrero, F. (Francisco), Mondragon Rezola, E. (Elisabet), Bergareche Yarza, J. A. (Jesus Alberto), Gorostidi Pagola, A. (Ana), de Munain Arregui, A. L. (Adolfo Lopez), Ruiz-Martinez, J. (Javier), Cerdan, D. (Debora), Duarte, J. (Jacinto), Clarimon, J. (Jordi), Dols-Icardo, O. (Oriol), Infante, J. (Jon), Marin, J. (Juan), Kulisevsky, J. (Jaime), Pagonabarraga, J. (Javier), Gonzalez-Aramburu, I. (Isabel), Sanchez Rodriguez, A. (Antonio), Sierra, M. (Mara), Duran, R. (Raquel), Ruz, C. (Clara), Vives, F. (Francisco), Escamilla-Sevilla, F. (Francisco), Minguez, A. (Adolfo), Camara, A. (Ana), Compta, Y. (Yaroslau), Ezquerra, M. (Mario), Jose Marti, M. (Maria), Fernandez, M. (Manel), Munoz, E. (Esteban), Fernandez-Santiago, R. (Ruben), Tolosa, E. (Eduard), Valldeoriola, F. (Francesc), Garcia-Ruiz, P. (Pedro), Gomez Heredia, M. J. (Maria Jose), Perez Errazquin, F. (Francisco), Hoenicka, J. (Janet), Jimenez-Escrig, A. (Adriano), Carlos Martinez-Castrillo, J. (Juan), Luis Lopez-Sendon, J. (Jose), Martinez Torres, I. (Irene), Tabernero, C. (Cesar), Vela, L. (Lydia), Zimprich, A. (Alexander), Pihlstrom, L. (Lasse), Koks, S. (Sulev), Taba, P. (Pille), Majamaa, K. (Kari), Siitonen, A. (Ari), Okubadejo, N. U. (Njideka U.), Ojo, O. O. (Oluwadamilola O.), Pitcher, T. (Toni), Anderson, T. (Tim), Bentley, S. (Steven), Fowdar, J. (Javed), Mellick, G. (George), Dalrymple-Alford, J. (John), Henders, A. K. (Anjali K.), Kassam, I. (Irfahan), Montgomery, G. (Grant), Sidorenko, J. (Julia), Zhang, F. (Futao), Xue, A. (Angli), Vallerga, C. L. (Costanza L.), Wallace, L. (Leanne), Wray, N. R. (Naomi R.), Yang, J. (Jian), Visscher, P. M. (Peter M.), Gratten, J. (Jacob), Silburn, P. A. (Peter A.), Halliday, G. (Glenda), Hickie, I. (Ian), Kwok, J. (John), Lewis, S. (Simon), Kennedy, M. (Martin), and Pearson, J. (John)

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.

Published
2019

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