268 results on '"Blauwendraat, C."'
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2. Polygenic resilience inheritance modulates the penetrance of Parkinson’s disease genetic risk factors
- Author
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LIU, H., primary, Dehestani, M., additional, Blauwendraat, C., additional, Makarious, M.B., additional, Leonard, H., additional, Kim, J.J., additional, Schulte, C., additional, Noyce, A., additional, Jacobs, B.M., additional, Foote, I., additional, Sharma, M., additional, Nalls, M., additional, Singleton, A., additional, Gasser, T., additional, and Bandres-Ciga, S., additional
- Published
- 2023
- Full Text
- View/download PDF
3. Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence from the COURAGE-PD Consortium
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Grover, S, Sreelatha, A, Pihlstrom, L, Domenighetti, C, Schulte, C, Sugier, P, Radivojkov-Blagojevic, M, Lichtner, P, Mohamed, O, Portugal, B, Landoulsi, Z, May, P, Bobbili, D, Edsall, C, Bartusch, F, Hanussek, M, Kruger, J, Hernandez, D, Blauwendraat, C, Mellick, G, Zimprich, A, Pirker, W, Tan, M, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Burbulla, L, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Pavelka, L, Van De Warrenburg, B, Bloem, B, Singleton, A, Aasly, J, Toft, M, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Krainc, D, Farrer, M, Kruger, R, Elbaz, A, Gasser, T, Sharma, M, Grover S., Sreelatha A. A. K., Pihlstrom L., Domenighetti C., Schulte C., Sugier P. -E., Radivojkov-Blagojevic M., Lichtner P., Mohamed O., Portugal B., Landoulsi Z., May P., Bobbili D., Edsall C., Bartusch F., Hanussek M., Kruger J., Hernandez D. G., Blauwendraat C., Mellick G. D., Zimprich A., Pirker W., Tan M., Rogaeva E., Lang A., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Burbulla L. F., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Pavelka L., Van De Warrenburg B. P. C., Bloem B. R., Singleton A. B., Aasly J., Toft M., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Krainc D., Farrer M. J., Kruger R., Elbaz A., Gasser T., Sharma M., Grover, S, Sreelatha, A, Pihlstrom, L, Domenighetti, C, Schulte, C, Sugier, P, Radivojkov-Blagojevic, M, Lichtner, P, Mohamed, O, Portugal, B, Landoulsi, Z, May, P, Bobbili, D, Edsall, C, Bartusch, F, Hanussek, M, Kruger, J, Hernandez, D, Blauwendraat, C, Mellick, G, Zimprich, A, Pirker, W, Tan, M, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Burbulla, L, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Pavelka, L, Van De Warrenburg, B, Bloem, B, Singleton, A, Aasly, J, Toft, M, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Krainc, D, Farrer, M, Kruger, R, Elbaz, A, Gasser, T, Sharma, M, Grover S., Sreelatha A. A. K., Pihlstrom L., Domenighetti C., Schulte C., Sugier P. -E., Radivojkov-Blagojevic M., Lichtner P., Mohamed O., Portugal B., Landoulsi Z., May P., Bobbili D., Edsall C., Bartusch F., Hanussek M., Kruger J., Hernandez D. G., Blauwendraat C., Mellick G. D., Zimprich A., Pirker W., Tan M., Rogaeva E., Lang A., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Burbulla L. F., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Pavelka L., Van De Warrenburg B. P. C., Bloem B. R., Singleton A. B., Aasly J., Toft M., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Krainc D., Farrer M. J., Kruger R., Elbaz A., Gasser T., and Sharma M.
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- 2022
4. Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence from the COURAGE-PD Consortium
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Grover, S. Sreelatha, A.A.K. Pihlstrom, L. Domenighetti, C. Schulte, C. Sugier, P.-E. Radivojkov-Blagojevic, M. Lichtner, P. Mohamed, O. Portugal, B. Landoulsi, Z. May, P. Bobbili, D. Edsall, C. Bartusch, F. Hanussek, M. Krüger, J. Hernandez, D.G. Blauwendraat, C. Mellick, G.D. Zimprich, A. Pirker, W. Tan, M. Rogaeva, E. Lang, A. Koks, S. Taba, P. Lesage, S. Brice, A. Corvol, J.-C. Chartier-Harlin, M.-C. Mutez, E. Brockmann, K. Deutschländer, A.B. Hadjigeorgiou, G.M. Dardiotis, E. Stefanis, L. Simitsi, A.M. Valente, E.M. Petrucci, S. Straniero, L. Zecchinelli, A. Pezzoli, G. Brighina, L. Ferrarese, C. Annesi, G. Quattrone, A. Gagliardi, M. Burbulla, L.F. Matsuo, H. Kawamura, Y. Hattori, N. Nishioka, K. Chung, S.J. Kim, Y.J. Pavelka, L. Van De Warrenburg, B.P.C. Bloem, B.R. Singleton, A.B. Aasly, J. Toft, M. Guedes, L.C. Ferreira, J.J. Bardien, S. Carr, J. Tolosa, E. Ezquerra, M. Pastor, P. Diez-Fairen, M. Wirdefeldt, K. Pedersen, N.L. Ran, C. Belin, A.C. Puschmann, A. Hellberg, C. Clarke, C.E. Morrison, K.E. Krainc, D. Farrer, M.J. Kruger, R. Elbaz, A. Gasser, T. Sharma, M. and Grover, S. Sreelatha, A.A.K. Pihlstrom, L. Domenighetti, C. Schulte, C. Sugier, P.-E. Radivojkov-Blagojevic, M. Lichtner, P. Mohamed, O. Portugal, B. Landoulsi, Z. May, P. Bobbili, D. Edsall, C. Bartusch, F. Hanussek, M. Krüger, J. Hernandez, D.G. Blauwendraat, C. Mellick, G.D. Zimprich, A. Pirker, W. Tan, M. Rogaeva, E. Lang, A. Koks, S. Taba, P. Lesage, S. Brice, A. Corvol, J.-C. Chartier-Harlin, M.-C. Mutez, E. Brockmann, K. Deutschländer, A.B. Hadjigeorgiou, G.M. Dardiotis, E. Stefanis, L. Simitsi, A.M. Valente, E.M. Petrucci, S. Straniero, L. Zecchinelli, A. Pezzoli, G. Brighina, L. Ferrarese, C. Annesi, G. Quattrone, A. Gagliardi, M. Burbulla, L.F. Matsuo, H. Kawamura, Y. Hattori, N. Nishioka, K. Chung, S.J. Kim, Y.J. Pavelka, L. Van De Warrenburg, B.P.C. Bloem, B.R. Singleton, A.B. Aasly, J. Toft, M. Guedes, L.C. Ferreira, J.J. Bardien, S. Carr, J. Tolosa, E. Ezquerra, M. Pastor, P. Diez-Fairen, M. Wirdefeldt, K. Pedersen, N.L. Ran, C. Belin, A.C. Puschmann, A. Hellberg, C. Clarke, C.E. Morrison, K.E. Krainc, D. Farrer, M.J. Kruger, R. Elbaz, A. Gasser, T. Sharma, M.
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- 2022
5. Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: A genome-wide association study
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Chia, R., Saez-Atienzar, S., Murphy, N., Chio, A., Blauwendraat, C., Roda, R. H., Tienari, P. J., Kaminski, H. J., Ricciardi, R., Guida, M., De Rosa, A., Petrucci, L., Evoli Stampanoni-B, Amelia, Provenzano, Carlo, Drachman, D. B., Traynor, B. J., Evoli A. (ORCID:0000-0003-0282-8787), Provenzano C. (ORCID:0000-0001-5476-5517), Chia, R., Saez-Atienzar, S., Murphy, N., Chio, A., Blauwendraat, C., Roda, R. H., Tienari, P. J., Kaminski, H. J., Ricciardi, R., Guida, M., De Rosa, A., Petrucci, L., Evoli Stampanoni-B, Amelia, Provenzano, Carlo, Drachman, D. B., Traynor, B. J., Evoli A. (ORCID:0000-0003-0282-8787), and Provenzano C. (ORCID:0000-0001-5476-5517)
- Abstract
Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genomewide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: A GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.
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- 2022
6. Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects
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Krohn, L., Heilbron, K., Blauwendraat, C., Reynolds, R. H., Yu, E., Senkevich, K., Rudakou, U., Estiar, M. A., Gustavsson, E. K., Brolin, K., Ruskey, J. A., Freeman, K., Asayesh, F., Chia, R., Arnulf, I., M. T. M., Hu, Montplaisir, J. Y., Gagnon, J. -F., Desautels, A., Dauvilliers, Y., Gigli, G. L., Valente, M., Janes, F., Bernardini, A., Hogl, B., Stefani, A., Ibrahim, A., Sonka, K., Kemlink, D., Oertel, W., Janzen, A., Plazzi, G., Biscarini, F., Antelmi, E., Figorilli, M., Puligheddu, M., Mollenhauer, B., Trenkwalder, C., Sixel-Doring, F., Cochen De Cock, V., Monaca, C. C., Heidbreder, A., Ferini-Strambi, L., Dijkstra, F., Viaene, M., Abril, B., Boeve, B. F., Aslibekyan, S., Auton, A., Babalola, E., Bell, R. K., Bielenberg, J., Bryc, K., Bullis, E., Coker, D., Partida, G. C., Dhamija, D., Das, S., Elson, S. L., Filshtein, T., Fletez-Brant, K., Fontanillas, P., Freyman, W., Gandhi, P. M., Hicks, B., Hinds, D. A., Jewett, E. M., Jiang, Y., Kukar, K., Lin, K. -H., Lowe, M., Mccreight, J. C., Mcintyre, M. H., Micheletti, S. J., Moreno, M. E., Mountain, J. L., Nandakumar, P., Noblin, E. S., O'Connell, J., Petrakovitz, A. A., Poznik, G. D., Schumacher, M., Shastri, A. J., Shelton, J. F., Shi, J., Shringarpure, S., Tran, V., Tung, J. Y., Wang, X., Wang, W., Weldon, C. H., Wilton, P., Hernandez, A., Wong, C., Tchakoute, C. T., Scholz, S. W., Ryten, M., Bandres-Ciga, S., Noyce, A., Cannon, P., Pihlstrom, L., Nalls, M. A., Singleton, A. B., Rouleau, G. A., Postuma, R. B., Gan-Or, Z., and 23andMe Research Team
- Subjects
Multidisciplinary ,Risk factors ,General Physics and Astronomy ,Genomics ,General Chemistry ,Human medicine ,Genome-wide association studies ,General Biochemistry, Genetics and Molecular Biology - Abstract
Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention. REM-sleep behavior disorder often precedes Parkinson's disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.
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- 2022
7. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
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Storm, Catherine S., Kia, Demis A., Almramhi, Mona M., Bandres-Ciga, Sara, Finan, Chris, Noyce, A. J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H. R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K. Y., Kinghorn, K. J., Lewis, P., Schreglmann, S. R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K. E., Clarke, C., Harvey, K., Jacobs, B. M., Brice, Alexis, Danjou, F., Lesage, S., Corvol, J. C., Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S. A., Cookson, M. R., Blauwendraat, C., Craig, D. W., Billingsley, K., Makarious, M. B., Narendra, D. P., Faghri, F., Gibbs, J. R., Hernandez, D. G., Van Keuren-Jensen, K., Shulman, J. M., Iwaki, H., Leonard, H. L., Nalls, M. A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N. E., Lungu, C., Singleton, A. B., Scholz, S. W., Reed, X., Uitti, R. J., Ross, O. A., Grenn, F. P., Moore, A., Alcalay, R. N., Wszolek, Z. K., Gan-Or, Z., Rouleau, G. A., Krohn, L., Mufti, K., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A. D., Aguilar Barberà, Miquel, Álvarez Angulo, Iñaki, Alvarez, V., Barrero, F. J., Yarza, J. A. B., Bernal-Bernal, I., Blázquez Estrada, M, Bonilla-Toribio, M., Botía, J. A., Boungiorno, M. T., Buiza-Rueda, Dolores, Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Y., Diez-Fairen, M., Dols-Icardo, Oriol, Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M. J. G., Gonzalez-Aramburu, I., Pagola, A. G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, Jaime, Labrador-Espinosa, M. A., Lopez-Sendon, J. L., de Munain Arregui, A. L., Macias, D., Torres, I. M., Marín, J., Marti, M. J., Martínez-Castrillo, J. C., Méndez-del-Barrio, C., González, M. M., Mata, M., Mínguez, A., Mir, P., Rezola, E. M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F. P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A. S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J. P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, Lydia, Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Koks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N. U., Ojo, O. O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T. L., Hingorani, Aroon, Wood, Nicholas W.., Universitat Autònoma de Barcelona, Rosetrees Trust, John Black Charitable Foundation, University College London, King Abdulaziz University, National Institute for Health Research (UK), Universidad de Cantabria, HUS Neurocenter, Department of Neurosciences, and Clinicum
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Aging ,Science ,Quantitative Trait Loci ,General Physics and Astronomy ,Neurodegenerative ,3124 Neurology and psychiatry ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cohort Studies ,Risk Factors ,Genetics research ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Genetic Predisposition to Disease ,Aetiology ,Multidisciplinary ,Genome ,Parkinson's Disease ,Genome, Human ,Prevention ,3112 Neurosciences ,Neurosciences ,Brain ,Genetic Variation ,Parkinson Disease ,General Chemistry ,Mendelian Randomization Analysis ,International Parkinson’s Disease Genomics Consortium ,Brain Disorders ,Good Health and Well Being ,Gene Expression Regulation ,Neurology ,5.1 Pharmaceuticals ,Case-Control Studies ,Neurological ,Disease Progression ,Development of treatments and therapeutic interventions ,Human ,Biotechnology - Abstract
Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.
- Published
- 2021
8. The use of a two-gene sequencing approach to accurately distinguish between the species within the Mycobacterium abscessus complex and Mycobacterium chelonae
- Author
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Blauwendraat, C., Dixon, G. L. J., Hartley, J. C., Foweraker, J., and Harris, K. A.
- Published
- 2012
- Full Text
- View/download PDF
9. Using global team science to identify genetic parkinson's disease worldwide
- Author
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Vollstedt, E, Kasten, M, Klein, C, Aasly, J, Adler, C, Ahmad-Annuar, A, Albanese, A, Alcalay, R, Al-Mubarak, B, Alvarez, V, Andree-Munoz, B, Annesi, G, Appel-Cresswell, S, Arkadir, D, Armasu, S, Barber, T, Bardien, S, Barkhuizen, M, Barrett, M, Basak, A, Beach, T, Benitez, B, Berg, D, Bhatia, K, Binkofski, F, Blauwendraat, C, Bonifati, V, Borges, V, Bozi, M, Brice, A, Brighina, L, Brockmann, K, Brucke, T, Bruggemann, N, Camacho, M, Cardoso, F, Belin, A, Carr, J, Chan, P, Chang-Castello, J, Chase, B, Chen-Plotkin, A, Ju Chung, S, Cilia, R, Clarimon, J, Clark, L, Cornejo-Olivas, M, Corvol, J, Cosentino, C, Cras, P, Crosiers, D, Damasio, J, Das, P, de Carvalho Aguiar, P, De Michele, G, De Rosa, A, Dieguez, E, Dorszewska, J, Erer, S, Ertan, S, Farrer, M, Fedotova, E, Ferese, R, Ferrarese, C, Ferraz, H, Fiala, O, Foroud, T, Friedman, A, Frigerio, R, Funayama, M, Gambardella, S, Garraux, G, Gatto, E, Genc, G, Giladi, N, Goldwurm, S, Gomez-Esteban, J, Gomez-Garre, P, Gorostidi, A, Grosset, D, Hanagasi, H, Hardy, J, Hassan, A, Hattori, N, Hauser, R, Hedera, P, Hentati, F, Hertz, J, Holton, J, Houlden, H, Hutz, M, Ikeuchi, T, Illarioshkin, S, Inca-Martinez, M, Infante, J, Jankovic, J, Jeon, B, Jesus, S, Jimenez-Del-Rio, M, Kaasinen, V, Kataoka, H, Kawakami, H, Kim, Y, Klivenyi, P, Koks, S, Konig, I, Kostic, V, Koziorowski, D, Kruger, R, Krygowska-Wajs, A, Kulisevsky, J, Lai, D, Lang, A, Ledoux, M, Lesage, S, Lim, S, Lin, C, Lohmann, K, Lopera, F, Lopez, G, Lu, C, Lynch, T, Machaczka, M, Madoev, H, Magalhaes, M, Majamaa, K, Maraganore, D, Marder, K, Markopoulou, K, Martikainen, M, Mata, I, Mazzetti, P, Mellick, G, Menendez-Gonzalez, M, Micheli, F, Mirelman, A, Mir, P, Morino, H, Morris, H, Munhoz, R, Naito, A, Olszewska, D, Ozelius, L, Padmanabhan, S, Paisan-Ruiz, C, Payami, H, Peluso, S, Petkovic, S, Petrucci, S, Pezzoli, G, Pimentel, M, Pirker, W, Pramstaller, P, Pulkes, T, Puschmann, A, Quattrone, A, Raggio, V, Ransmayr, G, Rieder, C, Riess, O, Rodriguez-Porcel, F, Rogaeva, E, Ross, O, Ruiz-Martinez, J, Sammler, E, San Luciano, M, Satake, W, Saunders-Pullman, R, Sazci, A, Scherzer, C, Schrag, A, Schumacher-Schuh, A, Sharma, M, Sidransky, E, Singleton, A, Petersen, M, Smolders, S, Spitz, M, Stefanis, L, Struhal, W, Sue, C, Swan, M, Swanberg, M, Taba, P, Taipa, R, Tan, M, Tan, A, Tan, E, Tang, B, Tayebi, N, Thaler, A, Thomas, A, Toda, T, Toft, M, Torres, L, Tumas, V, Valente, E, Van Broeckhoven, C, Vecsei, L, Velez-Pardo, C, Vidailhet, M, Warner, T, Williams-Gray, C, Winkelmann, J, Woitalla, D, Wood, N, Wszolek, Z, Wu, R, Wu, Y, Xie, T, Yoshino, H, Zhang, B, Zimprich, A, Vollstedt E. -J., Kasten M., Klein C., Aasly J., Adler C., Ahmad-Annuar A., Albanese A., Alcalay R. N., Al-Mubarak B., Alvarez V., Andree-Munoz B., Annesi G., Appel-Cresswell S., Arkadir D., Armasu S., Barber T. R., Bardien S., Barkhuizen M., Barrett M. J., Basak A. N., Beach T., Benitez B. A., Berg D., Bhatia K., Binkofski F., Blauwendraat C., Bonifati V., Borges V., Bozi M., Brice A., Brighina L., Brockmann K., Brucke T., Bruggemann N., Camacho M., Cardoso F., Belin A. C., Carr J., Chan P., Chang-Castello J., Chase B., Chen-Plotkin A., Ju Chung S., Cilia R., Clarimon J., Clark L., Cornejo-Olivas M., Corvol J. -C., Cosentino C., Cras P., Crosiers D., Damasio J., Das P., de Carvalho Aguiar P., De Michele G., De Rosa A., Dieguez E., Dorszewska J., Erer S., Ertan S., Farrer M., Fedotova E., Ferese R., Ferrarese C., Ferraz H., Fiala O., Foroud T., Friedman A., Frigerio R., Funayama M., Gambardella S., Garraux G., Gatto E. M., Genc G., Giladi N., Goldwurm S., Gomez-Esteban J. C., Gomez-Garre P., Gorostidi A., Grosset D., Hanagasi H., Hardy J., Hassan A., Hattori N., Hauser R. A., Hedera P., Hentati F., Hertz J. M., Holton J. L., Houlden H., Hutz M. H., Ikeuchi T., Illarioshkin S., Inca-Martinez M., Infante J., Jankovic J., Jeon B. S., Jesus S., Jimenez-Del-Rio M., Kaasinen V., Kataoka H., Kawakami H., Kim Y. J., Klivenyi P., Koks S., Konig I. R., Kostic V., Koziorowski D., Kruger R., Krygowska-Wajs A., Kulisevsky J., Lai D., Lang A., LeDoux M., Lesage S., Lim S. -Y., Lin C. -H., Lohmann K., Lopera F., Lopez G., Lu C. -S., Lynch T., Machaczka M., Madoev H., Magalhaes M., Majamaa K., Maraganore D., Marder K., Markopoulou K., Martikainen M. H., Mata I., Mazzetti P., Mellick G., Menendez-Gonzalez M., Micheli F., Mirelman A., Mir P., Morino H., Morris H., Munhoz R. P., Naito A., Olszewska D. A., Ozelius L. J., Padmanabhan S., Paisan-Ruiz C., Payami H., Peluso S., Petkovic S., Petrucci S., Pezzoli G., Pimentel M., Pirker W., Pramstaller P. P., Pulkes T., Puschmann A., Quattrone A., Raggio V., Ransmayr G., Rieder C., Riess O., Rodriguez-Porcel F., Rogaeva E., Ross O. A., Ruiz-Martinez J., Sammler E., San Luciano M., Satake W., Saunders-Pullman R., Sazci A., Scherzer C., Schrag A., Schumacher-Schuh A., Sharma M., Sidransky E., Singleton A. B., Petersen M. S., Smolders S., Spitz M., Stefanis L., Struhal W., Sue C. M., Swan M., Swanberg M., Taba P., Taipa R., Tan M., Tan A. H., Tan E. -K., Tang B., Tayebi N., Thaler A., Thomas A., Toda T., Toft M., Torres L., Tumas V., Valente E. M., Van Broeckhoven C., Vecsei L., Velez-Pardo C., Vidailhet M., Warner T. T., Williams-Gray C. H., Winkelmann J., Woitalla D., Wood N. W., Wszolek Z. K., Wu R. -M., Wu Y. -R., Xie T., Yoshino H., Zhang B., Zimprich A., Vollstedt, E, Kasten, M, Klein, C, Aasly, J, Adler, C, Ahmad-Annuar, A, Albanese, A, Alcalay, R, Al-Mubarak, B, Alvarez, V, Andree-Munoz, B, Annesi, G, Appel-Cresswell, S, Arkadir, D, Armasu, S, Barber, T, Bardien, S, Barkhuizen, M, Barrett, M, Basak, A, Beach, T, Benitez, B, Berg, D, Bhatia, K, Binkofski, F, Blauwendraat, C, Bonifati, V, Borges, V, Bozi, M, Brice, A, Brighina, L, Brockmann, K, Brucke, T, Bruggemann, N, Camacho, M, Cardoso, F, Belin, A, Carr, J, Chan, P, Chang-Castello, J, Chase, B, Chen-Plotkin, A, Ju Chung, S, Cilia, R, Clarimon, J, Clark, L, Cornejo-Olivas, M, Corvol, J, Cosentino, C, Cras, P, Crosiers, D, Damasio, J, Das, P, de Carvalho Aguiar, P, De Michele, G, De Rosa, A, Dieguez, E, Dorszewska, J, Erer, S, Ertan, S, Farrer, M, Fedotova, E, Ferese, R, Ferrarese, C, Ferraz, H, Fiala, O, Foroud, T, Friedman, A, Frigerio, R, Funayama, M, Gambardella, S, Garraux, G, Gatto, E, Genc, G, Giladi, N, Goldwurm, S, Gomez-Esteban, J, Gomez-Garre, P, Gorostidi, A, Grosset, D, Hanagasi, H, Hardy, J, Hassan, A, Hattori, N, Hauser, R, Hedera, P, Hentati, F, Hertz, J, Holton, J, Houlden, H, Hutz, M, Ikeuchi, T, Illarioshkin, S, Inca-Martinez, M, Infante, J, Jankovic, J, Jeon, B, Jesus, S, Jimenez-Del-Rio, M, Kaasinen, V, Kataoka, H, Kawakami, H, Kim, Y, Klivenyi, P, Koks, S, Konig, I, Kostic, V, Koziorowski, D, Kruger, R, Krygowska-Wajs, A, Kulisevsky, J, Lai, D, Lang, A, Ledoux, M, Lesage, S, Lim, S, Lin, C, Lohmann, K, Lopera, F, Lopez, G, Lu, C, Lynch, T, Machaczka, M, Madoev, H, Magalhaes, M, Majamaa, K, Maraganore, D, Marder, K, Markopoulou, K, Martikainen, M, Mata, I, Mazzetti, P, Mellick, G, Menendez-Gonzalez, M, Micheli, F, Mirelman, A, Mir, P, Morino, H, Morris, H, Munhoz, R, Naito, A, Olszewska, D, Ozelius, L, Padmanabhan, S, Paisan-Ruiz, C, Payami, H, Peluso, S, Petkovic, S, Petrucci, S, Pezzoli, G, Pimentel, M, Pirker, W, Pramstaller, P, Pulkes, T, Puschmann, A, Quattrone, A, Raggio, V, Ransmayr, G, Rieder, C, Riess, O, Rodriguez-Porcel, F, Rogaeva, E, Ross, O, Ruiz-Martinez, J, Sammler, E, San Luciano, M, Satake, W, Saunders-Pullman, R, Sazci, A, Scherzer, C, Schrag, A, Schumacher-Schuh, A, Sharma, M, Sidransky, E, Singleton, A, Petersen, M, Smolders, S, Spitz, M, Stefanis, L, Struhal, W, Sue, C, Swan, M, Swanberg, M, Taba, P, Taipa, R, Tan, M, Tan, A, Tan, E, Tang, B, Tayebi, N, Thaler, A, Thomas, A, Toda, T, Toft, M, Torres, L, Tumas, V, Valente, E, Van Broeckhoven, C, Vecsei, L, Velez-Pardo, C, Vidailhet, M, Warner, T, Williams-Gray, C, Winkelmann, J, Woitalla, D, Wood, N, Wszolek, Z, Wu, R, Wu, Y, Xie, T, Yoshino, H, Zhang, B, Zimprich, A, Vollstedt E. -J., Kasten M., Klein C., Aasly J., Adler C., Ahmad-Annuar A., Albanese A., Alcalay R. N., Al-Mubarak B., Alvarez V., Andree-Munoz B., Annesi G., Appel-Cresswell S., Arkadir D., Armasu S., Barber T. R., Bardien S., Barkhuizen M., Barrett M. J., Basak A. N., Beach T., Benitez B. A., Berg D., Bhatia K., Binkofski F., Blauwendraat C., Bonifati V., Borges V., Bozi M., Brice A., Brighina L., Brockmann K., Brucke T., Bruggemann N., Camacho M., Cardoso F., Belin A. C., Carr J., Chan P., Chang-Castello J., Chase B., Chen-Plotkin A., Ju Chung S., Cilia R., Clarimon J., Clark L., Cornejo-Olivas M., Corvol J. -C., Cosentino C., Cras P., Crosiers D., Damasio J., Das P., de Carvalho Aguiar P., De Michele G., De Rosa A., Dieguez E., Dorszewska J., Erer S., Ertan S., Farrer M., Fedotova E., Ferese R., Ferrarese C., Ferraz H., Fiala O., Foroud T., Friedman A., Frigerio R., Funayama M., Gambardella S., Garraux G., Gatto E. M., Genc G., Giladi N., Goldwurm S., Gomez-Esteban J. C., Gomez-Garre P., Gorostidi A., Grosset D., Hanagasi H., Hardy J., Hassan A., Hattori N., Hauser R. A., Hedera P., Hentati F., Hertz J. M., Holton J. L., Houlden H., Hutz M. H., Ikeuchi T., Illarioshkin S., Inca-Martinez M., Infante J., Jankovic J., Jeon B. S., Jesus S., Jimenez-Del-Rio M., Kaasinen V., Kataoka H., Kawakami H., Kim Y. J., Klivenyi P., Koks S., Konig I. R., Kostic V., Koziorowski D., Kruger R., Krygowska-Wajs A., Kulisevsky J., Lai D., Lang A., LeDoux M., Lesage S., Lim S. -Y., Lin C. -H., Lohmann K., Lopera F., Lopez G., Lu C. -S., Lynch T., Machaczka M., Madoev H., Magalhaes M., Majamaa K., Maraganore D., Marder K., Markopoulou K., Martikainen M. H., Mata I., Mazzetti P., Mellick G., Menendez-Gonzalez M., Micheli F., Mirelman A., Mir P., Morino H., Morris H., Munhoz R. P., Naito A., Olszewska D. A., Ozelius L. J., Padmanabhan S., Paisan-Ruiz C., Payami H., Peluso S., Petkovic S., Petrucci S., Pezzoli G., Pimentel M., Pirker W., Pramstaller P. P., Pulkes T., Puschmann A., Quattrone A., Raggio V., Ransmayr G., Rieder C., Riess O., Rodriguez-Porcel F., Rogaeva E., Ross O. A., Ruiz-Martinez J., Sammler E., San Luciano M., Satake W., Saunders-Pullman R., Sazci A., Scherzer C., Schrag A., Schumacher-Schuh A., Sharma M., Sidransky E., Singleton A. B., Petersen M. S., Smolders S., Spitz M., Stefanis L., Struhal W., Sue C. M., Swan M., Swanberg M., Taba P., Taipa R., Tan M., Tan A. H., Tan E. -K., Tang B., Tayebi N., Thaler A., Thomas A., Toda T., Toft M., Torres L., Tumas V., Valente E. M., Van Broeckhoven C., Vecsei L., Velez-Pardo C., Vidailhet M., Warner T. T., Williams-Gray C. H., Winkelmann J., Woitalla D., Wood N. W., Wszolek Z. K., Wu R. -M., Wu Y. -R., Xie T., Yoshino H., Zhang B., and Zimprich A.
- Published
- 2019
10. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
- Author
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Chia, R, Sabir, MS, Bandres-Ciga, S, Saez-Atienzar, S, Reynolds, RH, Gustavsson, E, Walton, RL, Ahmed, S, Viollet, C, Ding, JH, Makarious, MB, Diez-Fairen, M, Portley, MK, Shah, Z, Abramzon, Y, Hernandez, DG, Blauwendraat, C, Stone, DJ, Eicher, J, Parkkinen, L, Ansorge, O, Clark, L, Honig, LS, Marder, K, Lemstra, A, St George-Hyslop, P, Londos, E, Morgan, K, Lashley, T, Warner, TT, Jaunmuktane, Z, Galasko, D, Santana, I, Tienari, PJ, Myllykangas, L, Oinas, M, Cairns, NJ, Morris, JC, Halliday, GM, Van Deerlin, VM, Trojanowski, JQ, Grassano, M, Calvo, A, Mora, G, Canosa, A, Floris, G, Bohannan, RC, Brett, F, Gan-Or, Z, Geiger, JT, Moore, A, May, P, Kruger, R, Goldstein, DS, Lopez, G, Tayebi, N, Sidransky, E, Norcliffe-Kaufmann, L, Palma, JA, Kaufmann, H, Shakkottai, VG, Perkins, M, Newell, KL, Gasser, T, Schulte, C, Landi, F, Salvi, E, Cusi, D, Masliah, E, Kim, RC, Caraway, CA, Monuki, ES, Brunetti, M, Dawson, TM, Rosenthal, LS, Albert, MS, Pletnikova, O, Troncoso, JC, Flanagan, ME, Mao, QW, Bigio, EH, Rodriguez-Rodriguez, E, Infante, J, Lage, C, Gonzalez-Aramburu, I, Sanchez-Juan, P, Ghetti, B, Keith, J, Black, SE, Masellis, M, Rogaeva, E, Duyckaerts, C, Brice, A, Lesage, S, Xiromerisiou, G, Barrett, MJ, Tilley, BS, Gentleman, S, Logroscino, G, Serrano, GE, Beach, TG, McKeith, IG, Thomas, AJ, Attems, J, Morris, CM, Palmer, L, Love, S, Troakes, C, Al-Sarraj, S, Hodges, AK, Aarsland, D, Klein, G, Kaiser, SM, Woltjer, R, Pastor, P, Bekris, LM, Leverenz, JB, Besser, LM, Kuzma, A, Renton, AE, Goate, A, Bennett, DA, Scherzer, CR, Morris, HR, Ferrari, R, Albani, D, Pickering-Brown, S, Faber, K, Kukull, WA, Morenas-Rodriguez, E, Lleo, A, Fortea, J, Alcolea, D, Clarimon, J, Nalls, MA, Ferrucci, L, Resnick, SM, Tanaka, T, Foroud, TM, Graff-Radford, NR, Wszolek, ZK, Ferman, T, Boeve, BF, Hardy, JA, Topol, EJ, Torkamani, A, Singleton, AB, Ryten, M, Dickson, DW, Chio, A, Ross, OA, Gibbs, JR, Dalgard, CL, Traynor, BJ, Scholz, SW, and Amer Genome Ctr
- Subjects
hormones, hormone substitutes, and hormone antagonists - Abstract
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
- Published
- 2021
11. Investigation of autosomal genetic sex differences in Parkinson’s disease
- Author
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Blauwendraat, C. (Cornelis), Iwaki, H. (Hirotaka), Makarious, M. B. (Mary B.), Bandres-Ciga, S. (Sara), Leonard, H. L. (Hampton L.), Grenn, F. P. (Francis P.), Lake, J. (Julie), Krohn, L. (Lynne), Tan, M. (Manuela), Kim, J. J. (Jonggeol J.), Gibbs, J. R. (Jesse R.), Hernandez, D. G. (Dena G.), Ruskey, J. A. (Jennifer A.), Pihlstrom, L. (Lasse), Toft, M. (Mathias), van Hilten, J. J. (Jacobus J.), Marinus, J. (Johan), Schulte, C. (Claudia), Brockmann, K. (Kathrin), Sharma, M. (Manu), Siitonen, A. (Ari), Majamaa, K. (Kari), Eerola-Rautio, J. (Johanna), Tienari, P. J. (Pentti J.), Grosset, D. G. (Donald G.), Lesage, S. (Suzanne), Corvol, J.-C. (Jean-Christophe), Brice, A. (Alexis), Wood, N. (Nick), Hardy, J. (John), Gan-Or, Z. (Ziv), Heutink, P. (Peter), Gasser, T. (Thomas), Morris, H. R. (Huw R.), Noyce, A. J. (Alastair J.), Nalls, M. A. (Mike A.), and Singleton, A. B. (Andrew B.)
- Abstract
Objective: Parkinson’s disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson’s Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (similar to 20%). Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients.
- Published
- 2021
12. Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease
- Author
-
Blauwendraat, C, Iwaki, H, Makarious, MB, Bandres-Ciga, S, Leonard, HL, Grenn, FP, Lake, J, Krohn, L, Tan, M, Kim, JJ, Gibbs, JR, Hernandez, DG, Ruskey, JA, Pihlstrom, L, Toft, M, van Hilten, JJ, Marinus, J, Schulte, C, Brockmann, K, Sharma, M, Siitonen, A, Majamaa, K, Eerola-Rautio, J, Tienari, PJ, Grosset, DG, Lesage, S, Corvol, JC, Brice, A, Wood, N, Hardy, J, Gan-Or, Z, Heutink, P, Gasser, T, Morris, HR, Noyce, AJ, Nalls, MA, Singleton, AB, Clarimón J., Dols-Icardo, O, Kulisevsky J., Pagonabarraga, J, and Int Parkinsons Dis Genomics Consor
- Abstract
Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (similar to 20%). Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients.
- Published
- 2021
13. Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease
- Author
-
Leonard H, Lake J, Kim JJ, Gibbs JR, Ruskey JA, Pihlstrøm L, Eerola-Rautio J, Tienari PJ, Grosset DG, Wood N, Noyce AJ, Middlehurst B, Kia DA, Tan M, Houlden H, Storm CS, Morris HR, Plun-Favreau H, Holmans P, Hardy J, Trabzuni D, Quinn J, Bubb V, Mok KY, Kinghorn KJ, Wood NW, Lewis P, Schreglmann SR, Lovering R, R'Bibo L, Manzoni C, Rizig M, Ryten M, Guelfi S, Escott-Price V, Chelban V, Foltynie T, Williams N, Morrison KE, Clarke C, Harvey K, Jacobs BM, Brice A, Danjou F, Lesage S, Corvol JC, Martinez M, Schulte C, Brockmann K, Simón-Sánchez J, Heutink P, Rizzu P, Sharma M, Gasser T, Schneider SA, Cookson MR, Bandres-Ciga S, Blauwendraat C, Craig DW, Billingsley K, Makarious MB, Narendra DP, Faghri F, Hernandez DG, Van Keuren-Jensen K, Shulman JM, Iwaki H, Leonard HL, Nalls MA, Robak L, Bras J, Guerreiro R, Lubbe S, Troycoco T, Finkbeiner S, Mencacci NE, Lungu C, Singleton AB, Scholz SW, Reed X, Uitti RJ, Ross OA, Grenn FP, Moore A, Alcalay RN, Wszolek ZK, Gan-Or Z, Rouleau GA, Krohn L, Mufti K, van Hilten JJ, Marinus J, Adarmes-Gómez AD, Aguilar M, Alvarez I, Alvarez V, Barrero FJ, Yarza JAB, Bernal-Bernal I, Blazquez M, Bonilla-Toribio M, Botía JA, Boungiorno MT, Buiza-Rueda D, Cámara A, Carrillo F, Carrión-Claro M, Cerdan D, Clarimón J, Compta Y, Diez-Fairen M, Dols-Icardo O, Duarte J, Duran R, Escamilla-Sevilla F, Ezquerra M, Feliz C, Fernández M, Fernández-Santiago R, Garcia C, García-Ruiz P, Gómez-Garre P, Heredia MJG, Gonzalez-Aramburu I, Pagola AG, Hoenicka J, Infante J, Jesús S, Jimenez-Escrig A, Kulisevsky J, Labrador-Espinosa MA, Lopez-Sendon JL, de Munain Arregui AL, Macias D, Torres IM, Marín J, Marti MJ, Martínez-Castrillo JC, Méndez-Del-Barrio C, González MM, Mata M, Mínguez A, Mir P, Rezola EM, Muñoz E, Pagonabarraga J, Pastor P, Errazquin FP, Periñán-Tocino T, Ruiz-Martínez J, Ruz C, Rodriguez AS, Sierra M, Suarez-Sanmartin E, Tabernero C, Tartari JP, Tejera-Parrado C, Tolosa E, Valldeoriola F, Vargas-González L, Vela L, Vives F, Zimprich A, Pihlstrom L, Toft M, Taba P, Koks S, Hassin-Baer S, Majamaa K, Siitonen A, Tienari P, Okubadejo NU, Ojo OO, Kaiyrzhanov R, Shashkin C, Zharkinbekova N, Akhmetzhanov V, Kaishybayeva G, Karimova A, Khaibullin T, Lynch TL, and International Parkinson's Disease Genomics Consortium (IPDGC)
- Abstract
OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.
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- 2021
14. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)
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van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernandez, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleo, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illan-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodriguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodriguez Rodriguez, E., Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldo, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tarraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sorensen, T. I. A., Heutink, P., Sanchez-Juan, P., Posthuma, D., Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., Decarli, C., Geschwind, D. H., Clarimon, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., Holstege, H., Neurology, Epidemiology and Data Science, Human genetics, APH - Societal Participation & Health, APH - Aging & Later Life, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, and APH - Methodology
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education - Abstract
The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
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- 2020
15. Differences in the Presentation and Progression of Parkinson's Disease by Sex
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Iwaki, H., Blauwendraat, C., Leonard, H.L., Makarious, M.B., Kim, J.J., Liu, G., Maple-Grødem, J., Corvol, J.C., Pihlstrøm, L., Nimwegen, M.L. van, Smolensky, L., Amondikar, N., Hutten, S.J., Frasier, M., Nguyen, K.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. Van, Hernandez, D.G., Gibbs, R.J., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O.A., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P.C. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., Nalls, M.A., Iwaki, H., Blauwendraat, C., Leonard, H.L., Makarious, M.B., Kim, J.J., Liu, G., Maple-Grødem, J., Corvol, J.C., Pihlstrøm, L., Nimwegen, M.L. van, Smolensky, L., Amondikar, N., Hutten, S.J., Frasier, M., Nguyen, K.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. Van, Hernandez, D.G., Gibbs, R.J., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O.A., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P.C. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., and Nalls, M.A.
- Abstract
Item does not contain fulltext, BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.
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- 2021
16. Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
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Storm, C.S., Kia, D.A., Almramhi, M.M., Bandrés-Ciga, S., Finan, C., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K.Y., Kinghorn, K.J., Lewis, P., Schreglmann, S.R., Lovering, R., R’Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Harvey, K., Jacobs, B.M., Brice, A., Danjou, F., Lesage, S., Corvol, J-C, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S.A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Billingsley, K., Makarious, M.B., Narendra, D.P., Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A.B., Scholz, S.W., Reed, X., Uitti, R.J., Ross, O.A., Grenn, F.P., Moore, A., Alcalay, R.N., Wszolek, Z.K., Gan-Or, Z., Rouleau, G.A., Krohn, L., Mufti, K., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D., Aguilar, M., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botía, J.A., Boungiorno, M.T., Buiza-Rueda, D., Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, J., Compta, Y., Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., de Munain Arregui, A.L., Macias, D., Torres, I.M., Marín, J., Marti, M.J., Martínez-Castrillo, J.C., Méndez-del-Barrio, C., González, M.M., Mata, M., Mínguez, A., Mir, P., Rezola, E.M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F.P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Kõks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N.U., Ojo, O.O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T.L., Hingorani, A.D., Wood, N.W., Storm, C.S., Kia, D.A., Almramhi, M.M., Bandrés-Ciga, S., Finan, C., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Quinn, J., Bubb, V., Mok, K.Y., Kinghorn, K.J., Lewis, P., Schreglmann, S.R., Lovering, R., R’Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Harvey, K., Jacobs, B.M., Brice, A., Danjou, F., Lesage, S., Corvol, J-C, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Schneider, S.A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Billingsley, K., Makarious, M.B., Narendra, D.P., Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Bras, J., Guerreiro, R., Lubbe, S., Troycoco, T., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A.B., Scholz, S.W., Reed, X., Uitti, R.J., Ross, O.A., Grenn, F.P., Moore, A., Alcalay, R.N., Wszolek, Z.K., Gan-Or, Z., Rouleau, G.A., Krohn, L., Mufti, K., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D., Aguilar, M., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botía, J.A., Boungiorno, M.T., Buiza-Rueda, D., Cámara, A., Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, J., Compta, Y., Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernández, M., Fernández-Santiago, R., Garcia, C., García-Ruiz, P., Gómez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesús, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., de Munain Arregui, A.L., Macias, D., Torres, I.M., Marín, J., Marti, M.J., Martínez-Castrillo, J.C., Méndez-del-Barrio, C., González, M.M., Mata, M., Mínguez, A., Mir, P., Rezola, E.M., Muñoz, E., Pagonabarraga, J., Pastor, P., Errazquin, F.P., Periñán-Tocino, T., Ruiz-Martínez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Tolosa, E., Valldeoriola, F., Vargas-González, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Taba, P., Kõks, S., Hassin-Baer, S., Majamaa, K., Siitonen, A., Tienari, P., Okubadejo, N.U., Ojo, O.O., Shashkin, C., Zharkinbekova, N., Akhmetzhanov, V., Kaishybayeva, G., Karimova, A., Khaibullin, T., Lynch, T.L., Hingorani, A.D., and Wood, N.W.
- Abstract
Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.
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- 2021
17. Correction to: Large‑scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease
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Bandres-Ciga, S., Saez-Atienzar, S., Kim, J. J., Makarious, M. B., Faghri, F., Diez-Fairen, M., Iwaki, H., Leonard, H., Botia, J., Ryten, M., Hernandez, D., Gibbs, J. R., Ding, J., Gan-Or, Z., Noyce, A., Pihlstrom, L., Torkamani, A., Soltis, A. R., Dalgard, C. L., Scholz, S. W., Traynor, B. J., Ehrlich, D., Scherzer, C. R., Bookman, M., Cookson, M., Blauwendraat, C., Nalls, M. A., and Singleton, A. B.
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Multifactorial Inheritance ,Cellular and Molecular Neuroscience ,Dopaminergic Neurons ,Gene Expression Profiling ,Correction ,Humans ,Genetic Predisposition to Disease ,Parkinson Disease ,Neurology (clinical) ,Lysosomes ,Community Networks ,Mitochondria ,Pathology and Forensic Medicine - Abstract
Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.
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- 2021
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18. Association of a Common Genetic Variant with Parkinson’s Disease is Propagated through Microglia
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Langston, R. G., primary, Beilina, A., additional, Reed, X., additional, Singleton, A. B., additional, Blauwendraat, C., additional, Gibbs, J. R., additional, and Cookson, M. R., additional
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- 2021
- Full Text
- View/download PDF
19. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (vol 138, pg 237, 2019)
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van der Lee, SJ, Conway, OJ, Jansen, I, Carrasquillo, MM, Kleineidam, L, van den Akker, E, Hernandez, I, van Eijk, KR, Stringa, N, Chen, JSA, Zettergren, A, Andlauer, TFM, Diez-Fairen, M, Simon-Sanchez, J, Lleo, A, Zetterberg, H, Nygaard, M, Blauwendraat, C, Savage, JE, Mengel-From, J, Moreno-Grau, S, Wagner, M, Fortea, J, Keogh, MJ, Blennow, K, Skoog, I, Friese, MA, Pletnikova, O, Zulaica, M, Lage, C, de Rojas, I, Riedel-Heller, S, Illan-Gala, I, Wei, W, Jeune, B, Orellana, A, Bergh, FT, Wang, X, Hulsman, M, Beker, N, Tesi, N, Morris, CM, Indakoetxea, B, Collij, LE, Scherer, M, Morenas-Rodriguez, E, Ironside, JW, van Berckel, BNM, Alcolea, D, Wiendl, H, Strickland, SL, Pastor, P, Rodriguez, ER, Boeve, BF, Petersen, RC, Ferman, TJ, van Gerpen, JA, Reinders, MJT, Uitti, RJ, Tarraga, L, Maier, W, Dols-Icardo, O, Kawalia, A, Dalmasso, MC, Boada, M, Zettl, UK, van Schoor, NM, Beekman, M, Allen, M, Masliah, E, de Munain, AL, Pantelyat, A, Wszolek, ZK, Ross, OA, Dickson, DW, Graff-Radford, NR, Knopman, D, Rademakers, R, Lemstra, AW, Pijnenburg, YAL, Scheltens, P, Gasser, T, Chinnery, PF, Hemmer, B, Huisman, MA, Troncoso, J, Moreno, F, Nohr, EA, Sorensen, TIA, Heutink, P, Sanchez-Juan, P, Posthuma, D, Clarim?on, J, Christensen, K, Ertekin-Taner, N, Scholz, SW, Ramirez, A, Ruiz, A, Slagboom, E, van der Flier, WM, and Holstege, H
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education - Abstract
The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
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- 2020
20. Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information
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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.
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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).
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- 2020
21. Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts
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Iwaki, H., Blauwendraat, C., Leonard, H.L., Kim, J.J., Liu, G.Q., Maple-Grodem, J., Corvol, J.C., Pihlstrom, L., Nimwegen, M. van, Hutten, S.J., Nguyen, K.D.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. van, Hernandez, D.G., Gibbs, J.R., Chitrala, K.N., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., Nalls, M.A., and Int Parkinson's Dis Genomics Cons
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Parkinson's disease ,GBA ,Apolipoprotein E ,genomewide association study - Published
- 2019
22. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
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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
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- 2019
23. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease
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Fernandez-Santiago, R., Martin-Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres-Ciga, S., Manduchi, E., Tolosa, E., Singleton, A.B., Moore, J.H., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Schulte, C., Brockmann, K., Simoon-Saanchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Faghri, F., Gibbs, J.R., Hernandez, D.G., Keuren-Jensen, K. van, Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Scholz, S.W., Reed, X., Alcalay, R.N., Gan-Or, Z., Rouleau, G.A., Krohn, L., Hilten, J.J. van, Marinus, J., Adarmes-Goomez, A.D., Aguilar, I., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botia, J.A., Boungiorno, M.T., Buiza-Rueda, D., Camara, A., Carrillo, F., Carrion-Claro, M., Cerdan, D., Clarimon, J., Compta, Y., Casa, B. de la, Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernandez, M., Garcia, C., Garcia-Ruiz, P., Gomez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesus, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., Arregui, A.L.D., Macias, D., Torres, I.M., Marin, J., Marti, M.J., Martinez-Castrillo, C., Mendez-del-Barrio, C., Gonzalez, M.M., Mata, M., Minguez, A., Mir, P., Rezola, E.M., Munoz, E., Pagonabarraga, J., Pascual-Sedano, B., Pastor, P., Errazquin, F.P., Perinan-Tocino, T., Ruiz-Martinez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Valldeoriola, F., Vargas-Gonzalez, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Malagelada, C., Int Parkinson's Dis Genomics Conso, Fundació La Marató de TV3, Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), and Ministerio de Ciencia, Innovación y Universidades (España)
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0301 basic medicine ,epistasis ,Male ,Parkinson's disease ,very elderly ,alpha-synuclein ,Alpha‐synuclein ,regulatory associated protein of mTOR ,Cohort Studies ,0302 clinical medicine ,single nucleotide polymorphism ,genetics ,Age of Onset ,Genetics ,Aged, 80 and over ,Polymorphism, Single Nucleoti ,biology ,TOR Serine-Threonine Kinases ,target of rapamycin kinase ,fchsd1 gene ,Age at onset ,Chromosome Mapping ,glycogen synthase kinase 3beta ,Parkinson Disease ,Middle Aged ,cohort analysis ,LRRK2 ,priority journal ,Neurology ,chromosomal mapping ,neuromodulation ,mTOR ,alpha-Synuclein ,Female ,age at onset ,Signal Transduction ,onset age ,Adult ,MTOR protein, human ,protein kinase LKB1 ,gene locus ,Genotype ,multifactor dimensionality reduction ,SNP ,Single-nucleotide polymorphism ,rps6ka2 gene ,Polymorphism, Single Nucleotide ,Risk Assessment ,Article ,brain function ,03 medical and health sciences ,alpha synuclein ,medicine ,Humans ,controlled study ,Genetic Predisposition to Disease ,human ,ddc:610 ,SNCA protein, human ,gene ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,mammalian target of rapamycin ,Aged ,RPTOR ,Epistasis, Genetic ,Odds ratio ,medicine.disease ,major clinical study ,nervous system diseases ,030104 developmental biology ,mTOR signaling ,biology.protein ,Epistasis ,pathology ,Neurology (clinical) ,genetic predisposition ,030217 neurology & neurosurgery - Abstract
Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.
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- 2019
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24. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset
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Billingsley K.J., Barbosa I.A., Bandrés-Ciga S., Quinn J.P., Bubb V.J., Deshpande C., Botia J.A., Reynolds R.H., Zhang D., Simpson M.A., Blauwendraat C., Gan-Or Z., Gibbs J.R., Nalls M.A., Singleton A., Noyce A., Tucci A., Middlehurst B., Kia D., Tan M., Houlden H., Morris H.R., Plun-Favreau H., Holmans P., Hardy J., Trabzuni D., Bras J., Mok K., Kinghorn K., Wood N., Lewis P., Guerreiro R., Lovering 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., Simón-Sánchez 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-Gómez A., Aguilar M., Alvarez I., Alvarez V., Javier Barrero F., Bergareche Yarza J., Bernal-Bernal I., Blazquez M., Bernal M.B.-T., Boungiorno M., Buiza-Rueda D., Cámara A., Carcel M., Carrillo F., Carrión-Claro M., Cerdan D., Clarimón J., Compta Y., Diez-Fairen M., Dols-Icardo O., Duarte J., Duran R., Escamilla-Sevilla F., Ezquerra M., Fernández M., Fernández-Santiago R., Garcia C., García-Ruiz P., Gómez-Garre P., Heredia M.G., Gonzalez-Aramburu I., Pagola A.G., Hoenicka J., Infante J., Jesús S., Jimenez-Escrig A., Kulisevsky J., Labrador-Espinosa M., Lopez-Sendon J., de Munain Arregui A.L., Macias D., Torres I.M., Marín J., Marti M.J., Martínez-Castrillo J., Méndez-del-Barrio C., Menéndez González M., Mínguez A., Mir P., Rezola E.M., Muñoz E., Pagonabarraga J., Pastor P., Errazquin F.P., Periñán-Tocino T., Ruiz-Martínez J., Ruz C., Rodriguez A.S., Sierra M., Suarez-Sanmartin E., Tabernero C., Tartari J.P., Tejera-Parrado C., Tolosa E., Valldeoriola F., Vargas-González L., Vela L., Vives F., Zimprich A., Pihlstrom L., Taba P., Majamaa K., Siitonen A., Okubadejo N., Ojo O., Ryten M., and Koks S.
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genotype ,Mendelian randomization analysis ,CLN8 gene ,MUC1 gene ,genetic analysis ,bioenergy ,genetic risk ,genetic risk score ,Article ,ATG14 gene ,disorders of mitochondrial functions ,MRPS34 gene ,degenerative disease ,mitochondrial gene ,EP300 gene ,gene mutation ,human ,MPI gene ,gene ,molecular phylogeny ,LMBRD1 gene ,genome-wide association study ,monogenic disorder ,mitochondrial dynamics ,Parkinson disease ,E2F1 gene ,mitophagy ,CAPRIN2 gene ,priority journal ,risk factor ,LGALS3 gene ,disease exacerbation ,gene expression ,gene ontology ,meta analysis - 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 function-associated 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. © 2019, The Author(s).
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- 2019
25. Mitochondria function associated genes contribute to Parkinson’s disease risk and later age at onset
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Billingsley, K. J. (Kimberley J.), Barbosa, I. A. (Ines A.), Bandrés-Ciga, S. (Sara), Quinn, J. P. (John P.), Bubb, V. J. (Vivien J.), Deshpande, C. (Charu), Botia, J. A. (Juan A.), Reynolds, R. H. (Regina H.), Zhang, D. (David), Simpson, M. A. (Michael A.), Blauwendraat, C. (Cornelis), Gan-Or, Z. (Ziv), Raphael Gibbs, J. (J.), Nalls, M. A. (Mike A.), Singleton, A. (Andrew), Ryten, M. (Mina), and Koks, S. (Sulev)
- 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 function-associated 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. Additional information International Parkinson’s Disease Genomics Consortium (IPDGC) Members A. Noyce13, A. Tucci14, B. Middlehurst1, D. Kia15, M. Tan16, H. Houlden14, H. R. Morris16, H. Plun-Favreau14, P. Holmans17, J. Hardy14, D. Trabzuni14,18, J. Bras19, K. Mok14, K. Kinghorn20, N. Wood15, P. Lewis21, R. Guerreiro14,19, R. Lovering22, L. R’Bibo14, M. Rizig14, V. Escott-Price22,23, V. Chelban14, T. Foltynie6, N. Williams24, A. Brice25, F. Danjou25, S. Lesage25, M. Martinez26, A. Giri27,28, C. Schulte27,28, K. Brockmann27,28, J. Simón-Sánchez27,28, P. Heutink27,28, P. Rizzu28, M. Sharma29, T. Gasser27,28, A. Nicolas2, M. Cookson2, F. Faghri2,30, D. Hernandez2, J. Shulman31,32, L. Robak33, S. Lubbe34, S. Finkbeiner35,36,37, N. Mencacci38, C. Lungu39, S. Scholz40, X. Reed2, H. Leonard2, G. Rouleau7, L. Krohan41, J. van Hilten42, J. Marinus42, A. Adarmes-Gómez43, M. Aguilar44, I. Alvarez44, V. Alvarez45, F. Javier Barrero46, J. Bergareche Yarza47, I. Bernal-Bernal43, M. Blazquez45, M. Bonilla-Toribio Bernal43, M. Boungiorno44, Dolores Buiza-Rueda43, A. Cámara48, M. Carcel44, F. Carrillo43, M. Carrión-Claro43, D. Cerdan49, J. Clarimón50,51, Y. Compta48, M. Diez-Fairen44, O. Dols-Icardo50,51, J. Duarte49, R. l. Duran52, F. Escamilla-Sevilla53, M. Ezquerra48, M. Fernández48, R. Fernández-Santiago48, C. Garcia45, P. García-Ruiz54, P. Gómez-Garre43, M. Gomez Heredia55, I. Gonzalez-Aramburu56, A. Gorostidi Pagola57, J. Hoenicka58, J. Infante51,56, S. Jesús43, A. Jimenez-Escrig59, J. Kulisevsky51,60, M. Labrador-Espinosa43, J. Lopez-Sendon59, A. López de Munain Arregui59, D. Macias43, I. Martínez Torres61, J. Marín51,60, M. Jose Marti48, J. Martínez-Castrillo59, C. Méndez-del-Barrio43, M. Menéndez González43, A. Mínguez53, P. Mir43, E. Mondragon Rezola57, E. Muñoz48, J. Pagonabarraga51,60, P. Pastor44, F. Perez Errazquin55, T. Periñán-Tocino43, J. Ruiz-Martínez57, C. Ruz52, A. Sanchez Rodriguez56, M. Sierra56, E. Suarez-Sanmartin4, C. Tabernero59, J. Pablo Tartari44, C. Tejera-Parrado43, E. Tolosa48, F. Valldeoriola48, L. Vargas-González43, L. Vela62, F. Vives52, A. Zimprich63, L. Pihlstrom64, P. Taba65, K. Majamaa66,67, A. Siitonen66, N. Okubadejo68, O. Ojo68 1 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK 2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA 3Department of Medical and Molecular Genetics, King’s College London School of Basic and Medical Biosciences, London, SE1 9RT, UK 4Clinical Genetics Unit, Guys and St. Thomas’ NHS Foundation Trust, London, SE1 9RT, UK 5Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100, Murcia, Spain 6Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London, UK 7Montreal Neurological Institute, McGill University, Montréal, QC, Canada 8Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada 9Department of Human Genetics, McGill University, Montréal, QC, Canada 10Data Tecnica International, Glen Echo, MD, 20812, USA 11The Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA, 6009, Australia 12Centre for Comparative Genomics, Murdoch University, Murdoch, 6150, Australia 13Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, QMUL, London, UK 14Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 15UCL Genetics Institute; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 16Department of Clinical Neuroscience, University College London, London, UK 17Biostatistics & Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, UK 18Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia 19UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 20Institute of Healthy Ageing, University College London, London, UK 21University of Reading, Reading, UK 22University College London, London, UK 23MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, UK 24Cardiff University School of Medicine, Cardiff, UK 25Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France 26INSERM UMR 1220; and Paul Sabatier University, Toulouse, France 27Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 28DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany 29Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany 30Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA 31Departments of Neurology, Neuroscience, and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA 32Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA 33Baylor College of Medicine, Houston, TX, USA 34Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 35Departments of Neurology and Physiology, University of California, San Francisco, CA, USA 36Gladstone Institute of Neurological Disease, San Francisco, CA, USA 37Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, USA) 38 (Northwestern University Feinberg School of Medicine, Chicago, IL, USA) 39 (National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, USA) 40Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA 41Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada 42Department of Neurology, Leiden University Medical Center, Leiden, Netherlands 43Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Seville, Spain 44Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain 45Hospital Universitario Central de Asturias, Oviedo, Spain 46Hospital Universitario Parque Tecnologico de la Salud, Granada, Spain 47Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain 48Hospital Clinic de Barcelona, Barcelona, Spain 49Hospital General de Segovia, Segovia, Spain 50Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 51Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain 52Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain 53Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain 54Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain 55Hospital Universitario Virgen de la Victoria, Malaga, Spain 56Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain 57Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain 58Institut de Recerca Sant Joan de Déu, Barcelona, Spain 59Hospital Universitario Ramón y Cajal Madrid, Madrid, Spain 60Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 61Department of Neurology, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain 62Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain 63Department of Neurology, Medical University of Vienna, Vienna, Austria 64Department of Neurology, Oslo University Hospital, Oslo, Norway 65Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia 66Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland 67Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland 68University of Lagos, Yaba, Lagos State, Nigeria
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- 2019
26. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease
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Martin-Flores, N, Antonelli, F, Cerquera, C, Moreno, V, Manduchi, E, Moore, JH, Noyce, AJ, Kaiyrzhanov, R, Middlehurst, B, Kia, DA, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Quinn, J, Mok, KY, Kinghorn, KJ, Billingsley, K, Wood, NW, Lewis, P, Schreglmann, S, Guerreiro, R, Lovering, R, R'Bibo, L, Manzoni, C, Rizig, M, Ryten, M, Guelfi, S, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Morrison, KE, Clarke, C, Brice, A, Danjou, F, Lesage, S, Corvol, JC, Martinez, M, Schulte, C, Brockmann, K, Simoon-Saanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, MR, Bandres-Ciga, S, Blauwendraat, C, Craig, DW, Faghri, F, Gibbs, JR, Hernandez, DG, Van Keuren-Jensen, K, Shulman, JM, Iwaki, H, Leonard, HL, Nalls, MA, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, NE, Lungu, C, Singleton, AB, Scholz, SW, Reed, X, Alcalay, RN, Gan-Or, Z, Rouleau, GA, Krohn, L, van Hilten, JJ, Marinus, J, Adarmes-Goomez, AD, Aguilar, I, Alvarez, I, Alvarez, V, Barrero, FJ, Yarza, JAB, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio, M, Botia, JA, Boungiorno, MT, Buiza-Rueda, D, Camara, A, Carrillo, F, Carrion-Claro, M, Cerdan, D, Clarimon, J, Compta, Y, de la Casa, B, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, R, Escamilla-Sevilla, F, Feliz, C, Fernandez, M, Fernandez-Santiago, R, Garcia, C, Garcia-Ruiz, P, Gomez-Garre, P, Heredia, MJG, Gonzalez-Aramburu, I, Pagola, AG, Hoenicka, J, Infante, J, Jesus, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, MA, Lopez-Sendon, JL, Arregui, ALD, Macias, D, Torres, IM, Marin, J, Marti, MJ, Martinez-Castrillo, C, Mendez-del-Barrio, C, Gonzalez, MM, Mata, M, Minguez, A, Mir, P, Rezola, EM, Munoz, E, Pagonabarraga, J, Pascual-Sedano, B, Pastor, P, Errazquin, FP, Perinan-Tocino, T, Ruiz-Martinez, J, Ruz, C, Rodriguez, AS, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Tartari, JP, Tejera-Parrado, C, Tolosa, E, Valldeoriola, F, Vargas-Gonzalez, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Toft, M, Koks, S, Taba, P, Hassin-Baer, S, Ezquerra, M, Malagelada, C, and Int Parkinson's Dis Genomics Conso
- Subjects
epistasis ,alpha-synuclein ,Parkinson's disease ,mTOR ,SNP ,age at onset - Abstract
Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society
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- 2019
27. Moving beyond neurons:the role of cell type-specific gene regulation in Parkinson’s disease heritability
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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.
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- 2019
28. Genetic risk of Parkinson disease and progression: An analysis of 13 longitudinal cohorts
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Iwaki, Hirotaka, Blauwendraat, C., Leonard, Hampton L., Liu, Ganqiang, Maple-Grodem, Jodi, Corvol, Jean-Christophe, Nimwegen, M. van, Bloem, B.R., Warrenburg, B.P.C. van de, Singleton, A.B., Nalls, Mike A., Iwaki, Hirotaka, Blauwendraat, C., Leonard, Hampton L., Liu, Ganqiang, Maple-Grodem, Jodi, Corvol, Jean-Christophe, Nimwegen, M. van, Bloem, B.R., Warrenburg, B.P.C. van de, Singleton, A.B., and Nalls, Mike A.
- Abstract
Contains fulltext : 207890.pdf (publisher's version ) (Open Access)
- Published
- 2019
29. Using global team science to identify genetic Parkinson's disease worldwide
- Author
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Vollstedt, E‐J, Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad‐Annuar, A., Albanese, A., Alcalay, R., Al‐Mubarak, B., Alvarez, V., Andree‐Muñoz, B., Annesi, G., Appel‐Cresswell, S., Arkadir, D., Armasu, S., Barber, T.R., Bardien, S., Barkhuizen, M., Barrett, M.J., BaŞak, A.N., Beach, T., Benitez, B.A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brüggemann, N., Camacho, M., Cardoso, F., Belin, A.C., Carr, J., Chan, P., Chang‐Castello, J., Chase, B., Chen‐Plotkin, A., Chung, S.J., Cilia, R., Clarimon, J., Clark, L., Cornejo‐Olivas, M., Corvol, J‐C, Cosentino, C., Cras, P., Crosiers, D., Damásio, J., Das, P., Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E.M., Genç, G., Goldwurm, S., Gomez‐Esteban, J.C., Gómez‐Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R.A., Hedera, P., Hentati, F., Hertz, J.M., Holton, J.L., Houlden, H., Hutz, M.H., Ikeuchi, T., Illarioshkin, S., Inca‐Martinez, M., Infante, J., Jankovic, J., Jeon, B.S., Jesús, S., Jimenez‐Del‐Rio, M., Kataoka, H., Kawakami, H., Kim, Y.J., Klivényi, P., Kõks, S., König, I.R., KostiĆ, V., Koziorowski, D., Krüger, R., Krygowska‐Wajs, A., Kulisevsky, J., Lang, A., LeDoux, M., Lesage, S., Lim, S‐Y, Lin, C‐H, Lohmann, K., Lopera, F., Lopez, G., Lu, C‐S, Lynch, T., Machaczka, M., Madoev, H., Magalhães, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M.H., Mata, I., Mazzetti, P., Mellick, G., Menéndez‐González, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R.P., Naito, A., Olszewska, D.A., Ozelius, L.J., Padmanabhan, S., Paisán‐Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P.P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez‐Porcel, F., Rogaeva, E., Ross, O.A., Ruiz‐Martinez, J., Sammler, E., Luciano, M.S., Satake, W., Saunders‐Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher‐Schuh, A., Sharma, M., Sidransky, E., Singleton, A.B., Petersen, M.S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A.H., Tan, E‐K, Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E.M., Van Broeckhoven, C., Vecsei, L., Velez‐Pardo, C., Vidailhet, M., Warner, T.T., Williams‐Gray, C.H., Winkelmann, J., Woitalla, D., Wood, N.W., Wszolek, Z.K., Wu, R‐M, Wu, Y‐R, Xie, T., Yoshino, H., Zhang, B., Zimprich, A., Vollstedt, E‐J, Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad‐Annuar, A., Albanese, A., Alcalay, R., Al‐Mubarak, B., Alvarez, V., Andree‐Muñoz, B., Annesi, G., Appel‐Cresswell, S., Arkadir, D., Armasu, S., Barber, T.R., Bardien, S., Barkhuizen, M., Barrett, M.J., BaŞak, A.N., Beach, T., Benitez, B.A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brüggemann, N., Camacho, M., Cardoso, F., Belin, A.C., Carr, J., Chan, P., Chang‐Castello, J., Chase, B., Chen‐Plotkin, A., Chung, S.J., Cilia, R., Clarimon, J., Clark, L., Cornejo‐Olivas, M., Corvol, J‐C, Cosentino, C., Cras, P., Crosiers, D., Damásio, J., Das, P., Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E.M., Genç, G., Goldwurm, S., Gomez‐Esteban, J.C., Gómez‐Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R.A., Hedera, P., Hentati, F., Hertz, J.M., Holton, J.L., Houlden, H., Hutz, M.H., Ikeuchi, T., Illarioshkin, S., Inca‐Martinez, M., Infante, J., Jankovic, J., Jeon, B.S., Jesús, S., Jimenez‐Del‐Rio, M., Kataoka, H., Kawakami, H., Kim, Y.J., Klivényi, P., Kõks, S., König, I.R., KostiĆ, V., Koziorowski, D., Krüger, R., Krygowska‐Wajs, A., Kulisevsky, J., Lang, A., LeDoux, M., Lesage, S., Lim, S‐Y, Lin, C‐H, Lohmann, K., Lopera, F., Lopez, G., Lu, C‐S, Lynch, T., Machaczka, M., Madoev, H., Magalhães, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M.H., Mata, I., Mazzetti, P., Mellick, G., Menéndez‐González, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R.P., Naito, A., Olszewska, D.A., Ozelius, L.J., Padmanabhan, S., Paisán‐Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P.P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez‐Porcel, F., Rogaeva, E., Ross, O.A., Ruiz‐Martinez, J., Sammler, E., Luciano, M.S., Satake, W., Saunders‐Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher‐Schuh, A., Sharma, M., Sidransky, E., Singleton, A.B., Petersen, M.S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A.H., Tan, E‐K, Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E.M., Van Broeckhoven, C., Vecsei, L., Velez‐Pardo, C., Vidailhet, M., Warner, T.T., Williams‐Gray, C.H., Winkelmann, J., Woitalla, D., Wood, N.W., Wszolek, Z.K., Wu, R‐M, Wu, Y‐R, Xie, T., Yoshino, H., Zhang, B., and Zimprich, A.
- Abstract
Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well‐documented evidence, rapidly advancing and cost‐effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases...
- Published
- 2019
30. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease
- Author
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Bandrés-Ciga, S., Saez-Atienzar, S., Bonet-Ponce, L., Billingsley, K., Vitale, D., Blauwendraat, C., Gibbs, J.R., Pihlstrøm, L., Gan-Or, Z., Cookson, M.R., Nalls, M.A., Singleton, A.B., Kõks, S., Bandrés-Ciga, S., Saez-Atienzar, S., Bonet-Ponce, L., Billingsley, K., Vitale, D., Blauwendraat, C., Gibbs, J.R., Pihlstrøm, L., Gan-Or, Z., Cookson, M.R., Nalls, M.A., Singleton, A.B., and Kõks, S.
- Abstract
Background PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane‐trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway‐specific genetic risk factors is yet to be performed. Objectives To comprehensively study the role of the endocytic membrane‐trafficking pathway in the risk of PD. Methods Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane‐trafficking pathway including genome‐wide association studies data from 18,869 cases and 22,452 controls. We used pathway‐specific single‐nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow‐up functional studies, summary‐data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci. Results The heritability estimate attributed to endocytic membrane‐trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane‐trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane‐trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane‐trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane‐trafficking pathway genes showing functional consequence associated to PD risk. Conclusions We provide compelling genetic evidence that the endocytic membrane‐trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to
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- 2019
31. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset
- Author
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Billingsley, K.J., Barbosa, I.A., Bandrés-Ciga, S., Quinn, J.P., Bubb, V.J., Deshpande, C., Botia, J.A., Reynolds, R.H., Zhang, D., Simpson, M.A., Blauwendraat, C., Gan-Or, Z., Gibbs, J.R., Nalls, M.A., Singleton, A., Ryten, M., Kõks, S., Billingsley, K.J., Barbosa, I.A., Bandrés-Ciga, S., Quinn, J.P., Bubb, V.J., Deshpande, C., Botia, J.A., Reynolds, R.H., Zhang, D., Simpson, M.A., Blauwendraat, C., Gan-Or, Z., Gibbs, J.R., Nalls, M.A., Singleton, A., Ryten, M., and Kõks, S.
- 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 function-associated 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
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- 2019
32. Using global team science to identify genetic parkinson's disease worldwide
- Author
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Vollstedt, E. -J., Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad-Annuar, A., Albanese, Alberto, Alcalay, R. N., Al-Mubarak, B., Alvarez, V., Andree-Munoz, B., Annesi, G., Appel-Cresswell, S., Arkadir, D., Armasu, S., Barber, T. R., Bardien, S., Barkhuizen, M., Barrett, M. J., Basak, A. N., Beach, T., Benitez, B. A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brucke, T., Bruggemann, N., Camacho, M., Cardoso, F., Belin, A. C., Carr, J., Chan, P., Chang-Castello, J., Chase, B., Chen-Plotkin, A., Ju Chung, S., Cilia, R., Clarimon, J., Clark, L., Cornejo-Olivas, M., Corvol, J. -C., Cosentino, C., Cras, P., Crosiers, D., Damasio, J., Das, P., de Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E. M., Genc, G., Giladi, N., Goldwurm, S., Gomez-Esteban, J. C., Gomez-Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R. A., Hedera, P., Hentati, F., Hertz, J. M., Holton, J. L., Houlden, H., Hutz, M. H., Ikeuchi, T., Illarioshkin, S., Inca-Martinez, M., Infante, J., Jankovic, J., Jeon, B. S., Jesus, S., Jimenez-Del-Rio, M., Kaasinen, V., Kataoka, H., Kawakami, H., Kim, Y. J., Klivenyi, P., Koks, S., Konig, I. R., Kostic, V., Koziorowski, D., Kruger, R., Krygowska-Wajs, A., Kulisevsky, J., Lai, D., Lang, A., Ledoux, M., Lesage, S., Lim, S. -Y., Lin, C. -H., Lohmann, K., Lopera, F., Lopez, G., Lu, C. -S., Lynch, T., Machaczka, M., Madoev, H., Magalhaes, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M. H., Mata, I., Mazzetti, P., Mellick, G., Menendez-Gonzalez, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R. P., Naito, A., Olszewska, D. A., Ozelius, L. J., Padmanabhan, S., Paisan-Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P. P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez-Porcel, F., Rogaeva, E., Ross, O. A., Ruiz-Martinez, J., Sammler, E., San Luciano, M., Satake, W., Saunders-Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher-Schuh, A., Sharma, M., Sidransky, E., Singleton, A. B., Petersen, M. S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C. M., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A. H., Tan, E. -K., Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E. M., Van Broeckhoven, C., Vecsei, L., Velez-Pardo, C., Vidailhet, M., Warner, T. T., Williams-Gray, C. H., Winkelmann, J., Woitalla, D., Wood, N. W., Wszolek, Z. K., Wu, R. -M., Wu, Y. -R., Xie, T., Yoshino, H., Zhang, B., Zimprich, A., Albanese A. (ORCID:0000-0002-5864-0006), Vollstedt, E. -J., Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad-Annuar, A., Albanese, Alberto, Alcalay, R. N., Al-Mubarak, B., Alvarez, V., Andree-Munoz, B., Annesi, G., Appel-Cresswell, S., Arkadir, D., Armasu, S., Barber, T. R., Bardien, S., Barkhuizen, M., Barrett, M. J., Basak, A. N., Beach, T., Benitez, B. A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brucke, T., Bruggemann, N., Camacho, M., Cardoso, F., Belin, A. C., Carr, J., Chan, P., Chang-Castello, J., Chase, B., Chen-Plotkin, A., Ju Chung, S., Cilia, R., Clarimon, J., Clark, L., Cornejo-Olivas, M., Corvol, J. -C., Cosentino, C., Cras, P., Crosiers, D., Damasio, J., Das, P., de Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E. M., Genc, G., Giladi, N., Goldwurm, S., Gomez-Esteban, J. C., Gomez-Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R. A., Hedera, P., Hentati, F., Hertz, J. M., Holton, J. L., Houlden, H., Hutz, M. H., Ikeuchi, T., Illarioshkin, S., Inca-Martinez, M., Infante, J., Jankovic, J., Jeon, B. S., Jesus, S., Jimenez-Del-Rio, M., Kaasinen, V., Kataoka, H., Kawakami, H., Kim, Y. J., Klivenyi, P., Koks, S., Konig, I. R., Kostic, V., Koziorowski, D., Kruger, R., Krygowska-Wajs, A., Kulisevsky, J., Lai, D., Lang, A., Ledoux, M., Lesage, S., Lim, S. -Y., Lin, C. -H., Lohmann, K., Lopera, F., Lopez, G., Lu, C. -S., Lynch, T., Machaczka, M., Madoev, H., Magalhaes, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M. H., Mata, I., Mazzetti, P., Mellick, G., Menendez-Gonzalez, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R. P., Naito, A., Olszewska, D. A., Ozelius, L. J., Padmanabhan, S., Paisan-Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P. P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez-Porcel, F., Rogaeva, E., Ross, O. A., Ruiz-Martinez, J., Sammler, E., San Luciano, M., Satake, W., Saunders-Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher-Schuh, A., Sharma, M., Sidransky, E., Singleton, A. B., Petersen, M. S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C. M., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A. H., Tan, E. -K., Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E. M., Van Broeckhoven, C., Vecsei, L., Velez-Pardo, C., Vidailhet, M., Warner, T. T., Williams-Gray, C. H., Winkelmann, J., Woitalla, D., Wood, N. W., Wszolek, Z. K., Wu, R. -M., Wu, Y. -R., Xie, T., Yoshino, H., Zhang, B., Zimprich, A., and Albanese A. (ORCID:0000-0002-5864-0006)
- Abstract
Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well-documented evidence, rapidly advancing and cost-effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases. Although the importance of genetics for diagnosis and genetic counseling is undisputed, the recent development of first genetargeted therapies entering clinical trial1,2 is adding an important new layer to the (re-)consideration of genetic testing in neurology. However, establishing accurate genotype– phenotype and genotype–treatment relationships requires large sample sizes. Systematic reviews can serve as instruments to combine information from several small samples, but unfortunately, this is often complicated by inconsistent and incomplete reporting of clinical and genetic data across studies. Thus, large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.
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- 2019
33. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease
- Author
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Juge, P.-A. Lee, J.S. Ebstein, E. Furukawa, H. Dobrinskikh, E. Gazal, S. Kannengiesser, C. Ottaviani, S. Oka, S. Tohma, S. Tsuchiya, N. Rojas-Serrano, J. González-Pérez, M.I. Mejía, M. Buendía-Roldán, I. Falfán-Valencia, R. Ambrocio-Ortiz, E. Manali, E. Papiris, S.A. Karageorgas, T. Boumpas, D. Antoniou, K. Van Moorsel, C.H.M. Van Der Vis, J. De Man, Y.A. Grutters, J.C. Wang, Y. Borie, R. Wemeau-Stervinou, L. Wallaert, B. Flipo, R.-M. Nunes, H. Valeyre, D. Saidenberg-Kermanac'H, N. Boissier, M.-C. Marchand-Adam, S. Frazier, A. Richette, P. Allanore, Y. Sibilia, J. Dromer, C. Richez, C. Schaeverbeke, T. Lioté, H. Thabut, G. Nathan, N. Amselem, S. Soubrier, M. Cottin, V. Clément, A. Deane, K. Walts, A.D. Fingerlin, T. Fischer, A. Ryu, J.H. Matteson, E.L. Niewold, T.B. Assayag, D. Gross, A. Wolters, P. Schwarz, M.I. Holers, M. Solomon, J.J. Doyle, T. Rosas, I.O. Blauwendraat, C. Nalls, M.A. Debray, M.-P. Boileau, C. Crestani, B. Schwartz, D.A. Dieudé, P.
- Abstract
BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P = 9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P = 4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P = 1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P = 7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P = 2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. Copyright © 2018 Massachusetts Medical Society.
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- 2018
34. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases
- Author
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Witoelar, A, Jansen, IE, Wang, Y, Desikan, RS, Gibbs, JR, Blauwendraat, C, Thompson, WK, Hernandez, DG, Djurovic, S, Schork, AJ, Bettella, F, Ellinghaus, D, Franke, A, Lie, BA, McEvoy, LK, Karlsen, T, Lesage, S, Morris, HR, Brice, A, Wood, NW, Heutink, P, Hardy, J, Singleton, AB, Dale, AM, Gasser, T, Andreassen, OA, Sharma, M, Conso, IPDG, Amer, BECN, and Co, UKBE
- Published
- 2017
- Full Text
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35. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing
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Jansen, IE, Ye, H, Heetveld, S, Lechler, MC, Michels, H, Seinstra, RI, Lubbe, SJ, Drouet, V, Lesage, S, Majounie, E, Gibbs, JR, Nalls, MA, Ryten, M, Botia, JA, Vandrovcova, J, Simon-Sanchez, J, Castillo-Lizardo, M, Rizzu, P, Blauwendraat, C, Chouhan, AK, Li, Y, Yogi, P, Amin, N, van Duijn, CM, Morris, HR, Brice, A, Singleton, AB, David, DC, Nollen, EA, Jain, S, Shulman, JM, Heutink, P, Hernandez, DG, Arepalli, S, Brooks, J, Price, R, Nicolas, A, Chong, S, Cookson, MR, Dillman, A, Moore, M, Traynor, BJ, Plagnol, V, Nicholas, WW, Sheerin, UM, Jose, MB, Charlesworth, G, Gardner, M, Guerreiro, R, Trabzuni, D, Hardy, J, Sharma, M, Saad, M, Javier, S-S, Schulte, C, Corvol, JC, Dürr, A, Vidailhet, M, Sveinbjörnsdóttir, S, Barker, R, Caroline, HW-G, Ben-Shlomo, Y, Berendse, HW, van Dijk, KD, Berg, D, Brockmann, K, Wurster, I, Mätzler, W, Gasser, T, Martinez, M, de Bie, RMA, Biffi, A, and Velseboer, D
- Abstract
Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
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- 2017
36. Supplementary Material for: Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia
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Wilke, C., Gillardon, F., Deuschle, C., Hobert, M.A., Jansen, I.E., Metzger, F.G., Heutink, P., Gasser, T., Maetzler, W., Blauwendraat, C., and Synofzik, M.
- Subjects
mental disorders - Abstract
Background and Objective: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. Methods: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant). Results: Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant. Conclusions: Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.
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- 2016
- Full Text
- View/download PDF
37. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing
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Jansen, I.E., Ye, H., Heetveld, S., Lechler, M.C., Michels, H., Seinstra, R.I., Lubbe, S.J., Drouet, V., Lesage, S., Majounie, E., Gibbs, J.R., Nalls, M.A., Ryten, M., Botia, J.A., Vandrovcova, J., Simon-Sanchez, J., Castillo-Lizardo, M., Rizzu, P., Blauwendraat, C., Chouhan, A.K., Li, Y., Yogi, P., Amin, N., Duijn, C.M. van, Morris, H.R., Brice, A., Singleton, A.B., David, D.C., Nollen, E.A., Jain, S., Shulman, J.M., Heutink, P., Bloem, B., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, et al., Jansen, I.E., Ye, H., Heetveld, S., Lechler, M.C., Michels, H., Seinstra, R.I., Lubbe, S.J., Drouet, V., Lesage, S., Majounie, E., Gibbs, J.R., Nalls, M.A., Ryten, M., Botia, J.A., Vandrovcova, J., Simon-Sanchez, J., Castillo-Lizardo, M., Rizzu, P., Blauwendraat, C., Chouhan, A.K., Li, Y., Yogi, P., Amin, N., Duijn, C.M. van, Morris, H.R., Brice, A., Singleton, A.B., David, D.C., Nollen, E.A., Jain, S., Shulman, J.M., Heutink, P., Bloem, B., Post, B., Scheffer, H., Warrenburg, B.P.C. van de, and et al.
- Abstract
Contains fulltext : 169957.pdf (publisher's version ) (Open Access), BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced alpha-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
- Published
- 2017
38. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing
- Author
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Jansen, I. (Iris), Ye, H. (Hui), Heetveld, S. (Sasja), Lechler, M.C. (Marie C.), Michels, H. (Helen), Seinstra, R.I. (Renée I.), Lubbe, S.J. (Steven J.), Drouet, V. (Valérie), Lesage, S. (Suzanne), Majounie, E. (Elisa), Gibbs, J.R. (J.Raphael), Nalls, M.A. (Michael), Ryten, M. (Mina), Botia, J.A. (Juan A.), Vandrovcova, J. (Jana), Simón-Sánchez, J. (Javier), Castillo-Lizardo, M. (Melissa), Rizzu, P. (Patrizia), Blauwendraat, C. (Cornelis), Chouhan, A.K. (Amit K.), Li, Y. (Yarong), Yogi, P. (Puja), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Morris, H.R. (Huw R.), Brice, A. (Alexis), Singleton, A. (Andrew), David, D.C. (Della C.), Nollen, E.A. (Ellen A.), Jain, A. (Ashok), Shulman, J.M., Heutink, P. (Peter), Hernandez, D.G. (Dena), Arepalli, S. (Sampath), Brooks, J. (Janet), Price, R. (Ryan), Nicolas, A. (Aude), Chong, S. (Sean), Cookson, M.R. (Mark), Dillman, A. (Allissa), Moore, M. (Matt), Traynor, B.J. (Bryan), Plagnol, V. (Vincent), Nicholas W Wood, Sheerin, U.-M. (Una-Marie), Jose M Bras, Charlesworth, K. (Kate), Gardner, M. (Mac), Guerreiro, R. (Rita), Trabzuni, D. (Danyah), Hardy, J. (John), Sharma, M., Saad, M. (Mohamad), Javier Simón-Sánchez, Schulte, C. (Claudia), Corvol, J.C. (Jean-Christophe), Dürr, A. (Alexandra), Vidailhet, M. (M.), Sveinbjörnsdóttir, S. (Sigurlaug), Barker, R.A. (Roger), Caroline H Williams-Gray, Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Dijk, K.D. (Karin) van, Berg, D. (Daniela), Brockmann, K., Wurster, K.D. (Kathrin), Mätzler, W. (Walter), Gasser, T. (Thomas), Martinez, M. (Maria), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Velseboer, D. (Daan), Bloem, B.R. (Bastiaan), Post, B. (Bart), Wickremaratchi, M. (Mirdhu), Warrenburg, B. (Bart) van de, Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Pétursson, H. (Hjörvar), Riess, O. (Olaf), Burn, D.J. (David), Lubbe, S. (Steven), Cooper, J.M. (J Mark), McNeill, N.H. (Nathan), Schapira, A. (Anthony), Lungu, C. (Codrin), Chen, H. (Honglei), Dong, J. (Jing), Chinnery, P.F. (Patrick F.), Hudson, G. (Gavin), Clarke, C.E. (Carl E.), Moorby, C. (Catriona), Counsell, C. (Carl), Damier, P. (Philippe), Dartigues, J.-F., Deloukas, P. (Panagiotis), Gray, E. (Emma), Edkins, T. (Ted), Hunt, S.E. (Sarah E.), Potter, S.C. (Simon), Tashakkori-Ghanbaria, A. (Avazeh), Deuschl, G. (Günther), Lorenz, D. (Delia), Dexter, D.T. (David), Durif, F. (Frank), Evans, J. (Jonathan Mark), Langford, C. (Cordelia), Foltynie, T. (Thomas), Goate, A.M. (Alison), Harris, C. (Clare), Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Lambert, J.-C., O'Sullivan, S.S. (Sean), Revesz, T. (Tamas), Shaw, K. (Karen), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., Escott-Price, V. (Valentina), Pearson, J. (Justin), Williams, N. (Nigel), Mudanohwo, E. (Ese), Perlmutter, J.S. (Joel), Pollak, P. (Pierre), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Sawcer, S.J. (Stephen), Scheffer, H. (Hans), Shoulson, I. (Ira), Shulman, L. (Lee), Smith, C. (Colin), Walker, R. (Robert), Spencer, C.C.A. (Chris C.), Strange, A. (Amy), Stefansson, H. (Hreinn), Bettella, F. (Francesco), Zwart, J-A. (John-Anker), Stockton, J.D. (Joanna D.), Talbot, D., Tanner, C.M. (Carlie), Tison, F. (François), Winder-Rhodes, S. (Sophie), Bhatia, K.P. (Kailash), Jansen, I. (Iris), Ye, H. (Hui), Heetveld, S. (Sasja), Lechler, M.C. (Marie C.), Michels, H. (Helen), Seinstra, R.I. (Renée I.), Lubbe, S.J. (Steven J.), Drouet, V. (Valérie), Lesage, S. (Suzanne), Majounie, E. (Elisa), Gibbs, J.R. (J.Raphael), Nalls, M.A. (Michael), Ryten, M. (Mina), Botia, J.A. (Juan A.), Vandrovcova, J. (Jana), Simón-Sánchez, J. (Javier), Castillo-Lizardo, M. (Melissa), Rizzu, P. (Patrizia), Blauwendraat, C. (Cornelis), Chouhan, A.K. (Amit K.), Li, Y. (Yarong), Yogi, P. (Puja), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Morris, H.R. (Huw R.), Brice, A. (Alexis), Singleton, A. (Andrew), David, D.C. (Della C.), Nollen, E.A. (Ellen A.), Jain, A. (Ashok), Shulman, J.M., Heutink, P. (Peter), Hernandez, D.G. (Dena), Arepalli, S. (Sampath), Brooks, J. (Janet), Price, R. (Ryan), Nicolas, A. (Aude), Chong, S. (Sean), Cookson, M.R. (Mark), Dillman, A. (Allissa), Moore, M. (Matt), Traynor, B.J. (Bryan), Plagnol, V. (Vincent), Nicholas W Wood, Sheerin, U.-M. (Una-Marie), Jose M Bras, Charlesworth, K. (Kate), Gardner, M. (Mac), Guerreiro, R. (Rita), Trabzuni, D. (Danyah), Hardy, J. (John), Sharma, M., Saad, M. (Mohamad), Javier Simón-Sánchez, Schulte, C. (Claudia), Corvol, J.C. (Jean-Christophe), Dürr, A. (Alexandra), Vidailhet, M. (M.), Sveinbjörnsdóttir, S. (Sigurlaug), Barker, R.A. (Roger), Caroline H Williams-Gray, Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Dijk, K.D. (Karin) van, Berg, D. (Daniela), Brockmann, K., Wurster, K.D. (Kathrin), Mätzler, W. (Walter), Gasser, T. (Thomas), Martinez, M. (Maria), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Velseboer, D. (Daan), Bloem, B.R. (Bastiaan), Post, B. (Bart), Wickremaratchi, M. (Mirdhu), Warrenburg, B. (Bart) van de, Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Pétursson, H. (Hjörvar), Riess, O. (Olaf), Burn, D.J. (David), Lubbe, S. (Steven), Cooper, J.M. (J Mark), McNeill, N.H. (Nathan), Schapira, A. (Anthony), Lungu, C. (Codrin), Chen, H. (Honglei), Dong, J. (Jing), Chinnery, P.F. (Patrick F.), Hudson, G. (Gavin), Clarke, C.E. (Carl E.), Moorby, C. (Catriona), Counsell, C. (Carl), Damier, P. (Philippe), Dartigues, J.-F., Deloukas, P. (Panagiotis), Gray, E. (Emma), Edkins, T. (Ted), Hunt, S.E. (Sarah E.), Potter, S.C. (Simon), Tashakkori-Ghanbaria, A. (Avazeh), Deuschl, G. (Günther), Lorenz, D. (Delia), Dexter, D.T. (David), Durif, F. (Frank), Evans, J. (Jonathan Mark), Langford, C. (Cordelia), Foltynie, T. (Thomas), Goate, A.M. (Alison), Harris, C. (Clare), Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Lambert, J.-C., O'Sullivan, S.S. (Sean), Revesz, T. (Tamas), Shaw, K. (Karen), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., Escott-Price, V. (Valentina), Pearson, J. (Justin), Williams, N. (Nigel), Mudanohwo, E. (Ese), Perlmutter, J.S. (Joel), Pollak, P. (Pierre), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Sawcer, S.J. (Stephen), Scheffer, H. (Hans), Shoulson, I. (Ira), Shulman, L. (Lee), Smith, C. (Colin), Walker, R. (Robert), Spencer, C.C.A. (Chris C.), Strange, A. (Amy), Stefansson, H. (Hreinn), Bettella, F. (Francesco), Zwart, J-A. (John-Anker), Stockton, J.D. (Joanna D.), Talbot, D., Tanner, C.M. (Carlie), Tison, F. (François), Winder-Rhodes, S. (Sophie), and Bhatia, K.P. (Kailash)
- Abstract
Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
- Published
- 2017
- Full Text
- View/download PDF
39. NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases
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Blauwendraat, C., Faghri, F., Pihlstrom, L., Geiger, J. T., Elbaz, A., Lesage, S., Corvol, J. -C., May, P., Nicolas, A., Abramzon, Y., Murphy, N. A., Gibbs, J. R., Ryten, M., Ferrari, R., Bras, J., Guerreiro, R., Williams, J., Sims, R., Lubbe, S., Hernandez, D. G., Mok, K. Y., Robak, L., Campbell, R. H., Rogaeva, E., Traynor, B. J., Chia, R., Chung, S. J., Hardy, J. A., Brice, A., Wood, N. W., Houlden, H., Shulman, J. M., Morris, H. R., Gasser, T., Kruger, R., Heutink, P., Sharma, M., Simon-Sanchez, J., Nalls, M. A., Singleton, A. B., Scholz, S. W., Noyce, A. J., Giri, A., Oehmig, A., Tucci, A., Schulte, C., Cookson, M. R., Kia, D., Danjou, F., Charlesworth, G., Plun-Favreau, H., Holmans, P., Jansen, I., Hardy, J., Bras, J. M., Quinn, J., Botia, J. A., Billingsley, K., R'Bibo, L., Lungu, C., Martinez, M., Escott-Price, V., Mencacci, N. E., Topley, Lewis, Denny, P., Rizzu, P., Taba, P., Lovering, R., Ogalla, R. D., Foulger, R., Finkbeiner, S., Sveinbjornsdottir, S., Scholz, S., Koks, S., Foltynie, T., Price, T. R., Sheerin, U. -M., Williams, N., Reed, X., Wang, L., Brockmann, K., Oertel, W., Klein, C., Mohamed, F., Malard, L., Corti, O., Drouet, V., Goldwurm, S., Tesei, S., Canesi, M., Valente, E. M., Petrucci, S., Ginevrino, M., Toft, M., Aasly, J., Henriksen, S. P., Saetehaug, C., Orr-Urtreger, A., Giladi, N., Ferreira, J., Guedes, L. C., Bouca-Machado, R., Coelho, M., Rosa, M. M., Tolosa, E., Fernandez-Santiago, R., Ezquerra, M., Marti, M. J., Glaab, E., Balling, R., and Chung, S. -J.
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0301 basic medicine ,Aging ,methods [Genome-Wide Association Study] ,0302 clinical medicine ,Corticobasal degeneration ,neurodegenerative diseases ,humans ,risk ,high-throughput screening assays ,education.field_of_study ,General Neuroscience ,neurodegeneration ,genetics [Genetic Variation] ,3. Good health ,Neurochip ,alleles ,methods [Genotyping Techniques] ,Frontotemporal dementia ,Risk ,Population ,methods [High-Throughput Screening Assays] ,Computational biology ,Genetic screening ,genotyping ,NeuroChip ,NeuroX ,apolipoproteins E ,genetic variation ,genome-wide association study ,genotyping techniques ,Article ,Progressive supranuclear palsy ,03 medical and health sciences ,Apolipoproteins E ,medicine ,Humans ,Dementia ,ddc:610 ,education ,Genotyping ,Alleles ,business.industry ,medicine.disease ,030104 developmental biology ,genetics [Neurodegenerative Diseases] ,genetics [Apolipoproteins E] ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,Neuroscience ,030217 neurology & neurosurgery ,Imputation (genetics) ,Developmental Biology - Abstract
Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.
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- 2017
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40. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases
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Witoelar, A.W., Jansen, I.E., Wang, Y., Desikan, R.S., Gibbs, J.R., Blauwendraat, C., Thompson, W.K., Hernandez, D.G., Djurovic, S., Schork, A.J., Bettella, F., Ellinghaus, D., Franke, A., Lie, B.A., McEvoy, L.K., Karlsen, T.H., Lesage, S., Morris, H.R., Brice, A., Wood, N.W., Heutink, P., Hardy, J., Singleton, A.B., Dale, A.M., Gasser, T., Andreassen, O.A., Sharma, M., Nalls, M.A., Plagnol, V., Sheerin, U.M., Saad, M., Simon-Sanchez, J., Schulte, C., Sveinbjörnsdóttir, S., Arepalli, S., Barker, R.A., Ben-Shlomo, Y., Berendse, H.W., Berg, D., Bhatia, K.P., de Bie, R.M.A., Biffi, A., Bloem, B., Bochdanovits, Z., Bonin, M., Bras, J.M., Brockmann, K., Brooks, J.M., Burn, D.J., Majounie, E., Illig, T., Lichtner, P., Weale, M.E., Neurology, Amsterdam Neuroscience - Neurodegeneration, Human genetics, Hu, M, ANS - Neurodegeneration, ANS - Amsterdam Neuroscience, Intensive Care Medicine, AII - Inflammatory diseases, ANS - Neuroinfection & -inflammation, Graduate School, ACS - Amsterdam Cardiovascular Sciences, and APH - Aging & Later Life
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0301 basic medicine ,Aging ,genetics [Autoimmune Diseases] ,genetics [Colitis, Ulcerative] ,Ulcerative ,Genome-wide association study ,Disease ,Neurodegenerative ,North American Brain Expression Consortium ,Bioinformatics ,Arthritis, Rheumatoid ,International Parkinson’s Disease Genomics Consortium (IPDGC) ,0302 clinical medicine ,Crohn Disease ,genetics [Parkinson Disease] ,Risk Factors ,Pleiotropy ,Rheumatoid ,Pleiotropism ,2.1 Biological and endogenous factors ,Medicine ,genetics [Celiac Disease] ,Aetiology ,Original Investigation ,Parkinson's Disease ,Genetic Pleiotropy ,Parkinson Disease ,Colitis ,LRRK2 ,International Parkinson’s Disease Genomics Consortium ,Neurological ,Cognitive Sciences ,Type 1 ,Biotechnology ,genetics [Crohn Disease] ,Multiple Sclerosis ,genetics [Arthritis, Rheumatoid] ,Clinical Sciences ,Human leukocyte antigen ,genetics [Psoriasis] ,Autoimmune Disease ,Autoimmune Diseases ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Diabetes Mellitus ,Genetics ,Humans ,Psoriasis ,Genetic Predisposition to Disease ,ddc:610 ,Genetic association ,Neurology & Neurosurgery ,North American Brain Expression Consortium (NABEC) ,business.industry ,Arthritis ,Prevention ,Inflammatory and immune system ,Human Genome ,Inflammatory Bowel Disease ,genetics [Multiple Sclerosis] ,Neurosciences ,genetics [Diabetes Mellitus, Type 1] ,Brain Disorders ,Celiac Disease ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Genetic Loci ,and United Kingdom Brain Expression Consortium (UKBEC) Investigators ,Colitis, Ulcerative ,Neurology (clinical) ,Digestive Diseases ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Importance Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK , HLA-DRB5 , LRRK2 , and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA , LRRK2 , MAPT , TRIM10 , and SE TD1A in PD. Among the novel genes discovered, WNT3 , KANSL1 , CRHR1 , BOLA2 , and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. Conclusions and Relevance The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.
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- 2017
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41. Detection and serotyping of pneumococci in community acquired pneumonia patients without culture using blood and urine samples
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Elberse, K., Mens, S. van, Cremers, A.J., Meijvis, S.C.A., Vlaminckx, B., Jonge, M.I. de, Meis, J.F.G.M., Blauwendraat, C., Pol, I. van de, Schouls, L.M., Elberse, K., Mens, S. van, Cremers, A.J., Meijvis, S.C.A., Vlaminckx, B., Jonge, M.I. de, Meis, J.F.G.M., Blauwendraat, C., Pol, I. van de, and Schouls, L.M.
- Abstract
Contains fulltext : 154963.pdf (publisher's version ) (Open Access)
- Published
- 2015
42. Fine-mapping of SNCA variants in REM sleep behavior disorder identifies distinct associations
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Krohn, L., Wu, R., Ruskey, J., Laurent, S., Philstrom, L., Arnulf, I., Hu, M., Dauvilliers, Y., Hogl, B., Stefani, A., Holzknecht, E., Monaca, C., Beatriz, A., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Heidbreder, A., Cochen, V., Mollenhauer, B., Sonka, K., MICHELA FIGORILLI, Dijkstra, F., Viaene, M., Oertel, W., Gagnon, J., Nalls, M., Blauwendraat, C., Singleton, A., Desautels, A., Montplaisir, J., Ross, O., Boeve, B., Dupre, N., Fon, E., Postuma, R., Rouleau, G., and Gan-Or, Z.
43. Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies
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Edward A. Fon, Armaghan Alam, Richard Y.J. Wu, Cornelis Blauwendraat, Jennifer A. Ruskey, Luigi Ferini-Strambi, Paul Cannon, Mathias Toft, Mariarosaria Valente, Alex Desautels, Andrew B. Singleton, Valérie Cochen De Cock, Yves Dauvilliers, Elena Antelmi, C. Trenkwalder, Kari Anne Bjørnarå, Abril Beatriz, Christelle Charley Monaca, Jacques Montplaisir, Nicolas Dupré, Mineke Viaene, Peter Young, Birgit Högl, Giuseppe Plazzi, Monica Puligheddu, W. H. Oertel, Marco Toffoli, Bradley F. Boeve, Owen A. Ross, Friederike Sixel-Döring, Lasse Pihlstrøm, Michele T.M. Hu, Isabelle Arnulf, Sandra B. Laurent, Karl Heilbron, Michela Figorilli, Anna Heidbreder, Lynne Krohn, Guy A. Rouleau, Karel Sonka, Ziv Gan-Or, Mike A. Nalls, Jean-François Gagnon, David Kemlink, Evi Holzknecht, Femke Dijkstra, Ambra Stefani, Gian Luigi Gigli, Brit Mollenhauer, Ronald B. Postuma, Krohn L., Wu R.Y.J., Heilbron K., Ruskey J.A., Laurent S.B., Blauwendraat C., Alam A., Arnulf I., Hu M.T.M., Dauvilliers Y., Hogl B., Toft M., Bjornara K.A., Stefani A., Holzknecht E., Monaca C.C., Abril B., Plazzi G., Antelmi E., Ferini-Strambi L., Young P., Heidbreder A., Cochen De Cock V., Mollenhauer B., Sixel-Doring F., Trenkwalder C., Sonka K., Kemlink D., Figorilli M., Puligheddu M., Dijkstra F., Viaene M., Oertel W., Toffoli M., Gigli G.L., Valente M., Gagnon J.-F., Nalls M.A., Singleton A.B., Desautels A., Montplaisir J.Y., Cannon P., Ross O.A., Boeve B.F., Dupre N., Fon E.A., Postuma R.B., Pihlstrom L., Rouleau G.A., Gan-Or Z., Krohn, L., R. Y. J., Wu, Heilbron, K., Ruskey, J. A., Laurent, S. B., Blauwendraat, C., Alam, A., Arnulf, I., M. T. M., Hu, Dauvilliers, Y., Hogl, B., Toft, M., Bjornara, K. A., Stefani, A., Holzknecht, E., Monaca, C. C., Abril, B., Plazzi, G., Antelmi, E., Ferini-Strambi, L., Young, P., Heidbreder, A., Cochen De Cock, V., Mollenhauer, B., Sixel-Doring, F., Trenkwalder, C., Sonka, K., Kemlink, D., Figorilli, M., Puligheddu, M., Dijkstra, F., Viaene, M., Oertel, W., Toffoli, M., Gigli, G. L., Valente, M., Gagnon, J. -F., Nalls, M. A., Singleton, A. B., Desautels, A., Montplaisir, J. Y., Cannon, P., Ross, O. A., Boeve, B. F., Dupre, N., Fon, E. A., Postuma, R. B., Pihlstrom, L., Rouleau, G. A., Gan-Or, Z., McGill University Health Center [Montreal] (MUHC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Imperial College London, 23andMe Inc., National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Oxford [Oxford], Nuffield Department of Clinical Neurosciences [Oxford], Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Innsbruck Medical University [Austria] (IMU), Oslo University Hospital [Oslo], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Alma Mater Studiorum University of Bologna (UNIBO), University of Bologna, Department of Biomedical and Neuromotor Sciences [Bologna, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), University of Münster, Clinique Beau Soleil [Montpellier], EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Paracelsus-Elena-Klinik, Kassel, Germany., University Medical Center Göttingen (UMG), First Faculty of Medicine Charles University [Prague], Universita degli Studi di Cagliari [Cagliari], Algemeen Ziekenhuis Sint-Dimpna, Philipps University of Marburg, Università degli Studi di Udine - University of Udine [Italie], University College of London [London] (UCL), Department of Mathematics and Computer Science [Udine], Hôpital du Sacré-Coeur de Montréal, Université du Québec à Montréal = University of Québec in Montréal (UQAM), Data Tecnica International, Centre d'études avancées en Médecine du Sommeil (CEAMS), Université de Montréal (UdeM)-Hôpital du Sacré-Coeur de Montréal, Mayo Clinic [Jacksonville], Mayo Clinic [Rochester], Laval University Medical center, and Université Laval [Québec] (ULaval)
- Subjects
Male ,0301 basic medicine ,Oncology ,Linkage disequilibrium ,Synucleinopathies ,REM sleep behavior disorder ,MESH: Logistic Models ,REM Sleep Behavior Disorder ,0302 clinical medicine ,synucleinopathy ,SNCA ,Odds Ratio ,RBD-specific risk variants ,MESH: Aged ,MESH: Middle Aged ,Rapid eye movement sleep behavior disorder (RBD) ,MESH: Polymorphism, Single Nucleotide ,MESH: Genetic Predisposition to Disease ,Parkinson Disease ,Middle Aged ,MESH: Case-Control Studies ,3. Good health ,Neurology ,MESH: Synucleinopathies ,alpha-Synuclein ,Female ,Adult ,Lewy Body Disease ,medicine.medical_specialty ,Prodromal Symptoms ,Single-nucleotide polymorphism ,Locus (genetics) ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Internal medicine ,MESH: alpha-Synuclein ,medicine ,Humans ,Genetic Predisposition to Disease ,MESH: Prodromal Symptoms ,Allele frequency ,MESH: Lewy Body Disease ,Aged ,MESH: Humans ,business.industry ,Dementia with Lewy bodies ,[SCCO.NEUR]Cognitive science/Neuroscience ,MESH: Adult ,Odds ratio ,medicine.disease ,MESH: Odds Ratio ,MESH: Male ,synucleinopathies ,Logistic Models ,030104 developmental biology ,MESH: REM Sleep Behavior Disorder ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Case-Control Studies ,Synuclein ,Neurology (clinical) ,business ,MESH: Female ,MESH: Parkinson Disease ,030217 neurology & neurosurgery - Abstract
Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.
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- 2020
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44. The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.
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Dilliott AA, Costanzo MC, Bandres-Ciga S, Blauwendraat C, Casey B, Hoang Q, Iwaki H, Jang D, Kim JJ, Leonard HL, Levine KS, Makarious M, Nguyen TT, Rouleau GA, Singleton AB, Smadbeck P, Solle J, Vitale D, Nalls M, Flannick J, Burtt NP, and Farhan SMK
- Abstract
Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease., Competing Interests: Participation of H.L. Leonard, D. Vitale, H. Iwaki, and M.A. Nalls in this project was part of a competitive contract awarded to Data Tecnica International LLC by the NIH to support open-science research. M.A. Nalls also currently serves on the scientific advisory board for Clover Therapeutics and is a scientific founder at Neuron23 Inc; he also owns stocks. Go to Neurology.org/NG for full disclosures., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2025
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45. Genetic regulation of TERT splicing affects cancer risk by altering cellular longevity and replicative potential.
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Florez-Vargas O, Ho M, Hogshead MH, Papenberg BW, Lee CH, Forsythe K, Jones K, Luo W, Teshome K, Blauwendraat C, Billingsley KJ, Kolmogorov M, Meredith M, Paten B, Chari R, Zhang C, Schneekloth JS, Machiela MJ, Chanock SJ, Gadalla SM, Savage SA, Mbulaiteye SM, and Prokunina-Olsson L
- Subjects
- Humans, Introns genetics, Polymorphism, Single Nucleotide, Cell Proliferation genetics, Cell Line, Tumor, Genetic Predisposition to Disease, Apoptosis genetics, Alleles, G-Quadruplexes, CRISPR-Cas Systems, Telomerase genetics, Telomerase metabolism, Neoplasms genetics, Genome-Wide Association Study, Minisatellite Repeats genetics, Alternative Splicing genetics
- Abstract
The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2025
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46. The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.
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Chen Z, Alvarez Jerez P, Anderson C, Paucar M, Lee J, Nilsson D, Macpherson H, Scardamaglia A, Montgomery K, Hardy J, Singleton AB, Tucci A, Mathews KD, Fu YH, Engvall M, Laffita-Mesa J, Nennesmo I, Wedell A, Ptáček LJ, Blauwendraat C, Gustavsson EK, Svenningsson P, Ryten M, and Houlden H
- Subjects
- Humans, Male, Female, Sweden, Homeodomain Proteins genetics, Pedigree, Machado-Joseph Disease genetics, Haplotypes, Spinocerebellar Ataxias genetics, Middle Aged, Utah, Adult, Trinucleotide Repeat Expansion genetics, Founder Effect
- Abstract
Background: The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders., Methods: Given that the pathogenic repeat expansion is rare on a population level, we proposed a common ancestor across all families. Here, we employed targeted long-read sequencing through adaptive sampling, enriching for the chr16q22 region of interest., Results: Using phased sequencing results from individuals from Utah, Iowa, and Southern Sweden, we confirmed a common ~2000-year-old ancestral haplotype harbouring the repeat expansion., Conclusion: This study provides further insight into the genetic architecture of SCA4. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
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- 2025
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47. Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson's disease risk.
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Chew EG, Liu Z, Li Z, Chung SJ, Lian MM, Tandiono M, Heng YJ, Ng EY, Tan LC, Chng WL, Tan TJ, Peh EK, Ho YS, Chen XY, Lim EY, Chang CH, Leong JJ, Peh TX, Chan LL, Chao Y, Au WL, Prakash KM, Lim JL, Tay YW, Mok V, Chan AY, Lin JJ, Jeon BS, Song K, Tham CC, Pang CP, Ahn J, Park KH, Wiggs JL, Aung T, Tan AH, Ahmad Annuar A, Makarious MB, Blauwendraat C, Nalls MA, Robak LA, Alcalay RN, Gan-Or Z, Reynolds R, Lim SY, Xia Y, Khor CC, Tan EK, Wang Z, and Foo JN
- Subjects
- Humans, Glucosylceramidase genetics, Male, Female, Genetic Variation genetics, Case-Control Studies, Exome genetics, Aged, Risk Factors, Middle Aged, Parkinson Disease genetics, Parkinson Disease epidemiology, Asian People genetics, Genetic Predisposition to Disease, Exome Sequencing methods
- Abstract
Parkinson's disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10
-15 ) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10-8 ). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease., Competing Interests: Competing interests: Z.G.-O. received consultancy fees from Lysosomal Therapeutics, Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua Bio, Congruence Therapeutics, Takeda, Jazz Pharmaceuticals, Guidepoint, Lighthouse and Deerfield. R.N.A. received consultation fees from Biogen, Biohaven, Capsida, Gain Therapeutics, Genzyme/Sanofi, Janssen, Servier, SK Biopharmaceuticals, Takeda and Vanqua Bio. Y.X. holds a stock option in NeoCytogen Therapeutics where she is scientific co-founder and Chief Scientific Officer. M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica, LLC by the National Institutes of Health to support open science research. M.A.N. also owns stock in Character Bio, Inc. and Neuron23, Inc. The other authors declare no competing interests., (© 2024. The Author(s).)- Published
- 2025
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48. Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.
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Akçimen F, Paquette K, Crea PW, Saffie-Awad P, Achoru C, Taiwo F, Ozomma S, Onwuegbuzie G, Khani M, Grant S, Owolabi L, Okereke C, Oshinaike O, Iwuozo E, Lee PS, Oyakhire S, Osemwegie N, Daida K, Abubakar S, Olusanya A, Isayan M, Traurig R, Ogunmodede A, Samuel S, Makarious MB, Sa'ad F, Olanigan R, Levine K, Ogbimi EM, Vitale D, Odiase F, Koretsky MJ, Ojini F, Odeniyi O, Fang ZH, Obianozie N, Hall DA, Nwazor E, Xie T, Nwaokorie F, Padmanaban M, Nwani P, Shamim EA, Nnama A, Standaert D, Komolafe M, Dean M, Osaigbovo G, Disbrow E, Ishola I, Rawls A, Imarhiagbe F, Chandra S, Erameh C, Hinson V, Louie N, Idowu A, Solle J, Norris SA, Ibrahim A, Kilbane C, Sukumar G, Shulman LM, Ezuduemoih D, Staisch J, Breaux S, Dalgard C, Foster ER, Bello A, Ameri A, Real R, Ikwenu E, Morris HR, Anyanwu R, Stimming EF, Billingsley K, Alaofin W, Jerez PA, Agabi O, Hernandez DG, Akinyemi R, Arepalli S, Malik L, Owolabi R, Nyandaiti Y, Leonard HL, Wahab K, Step K, Abiodun O, Hernandez CF, Abdulai F, Iwaki H, Bardien S, Klein C, Hardy J, Houlden H, Galvelis KG, Nalls MA, Dahodwala N, Aamodt W, Hill E, Espay A, Factor S, Branson C, Blauwendraat C, Singleton AB, Ojo O, Chahine LM, Okubadejo N, and Bandres-Ciga S
- Abstract
Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which - p.Glu268Ala and p.Arg1538Cys - had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups., Competing Interests: Competing interests KL, DV, HLL, HI, MJK and MAN declare that they are consultants employed by DataTecnica LLC, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company. MAN also owns stock from Neuron23 Inc and Character Biosciences.
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- 2025
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49. The effect of polygenic risk score on PD risk and phenotype in LRRK2 G2019S and GBA1 carriers.
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Goldstein O, Shani S, Gana-Weisz M, Elkoshi N, Casey F, Sun YH, Chandratre K, Cedarbaum JM, Blauwendraat C, Bar-Shira A, Thaler A, Gurevich T, Mirelman A, Giladi N, Orr-Urtreger A, and Alcalay RN
- Abstract
Background: While LRRK2 and GBA1 variants are associated with Parkinson's disease (PD), most carriers will not develop the disease., Objective: To test if polygenic risk score (PRS) modifies disease risk and phenotypes in LRRK2 G2019S carriers, GBA1 carriers, and non-carriers (NC)., Methods: We genotyped 786 participants using Illumina's NeuroBooster-array (NBA) and sequenced the genome of 244, all of Ashkenazi ancestry (AJ), and calculated PRS to test its effects on clinically- and biologically-defined disease risk and phenotypes (n = 715). Among LRRK2 G2019S PD, we tested PRS association with α-synuclein seed-amplification-assay (n = 11). We used the PPMI and AMP-PD databases as validation cohorts., Results: In clinically-defined PD, PRS significantly modified disease risk in GBA1 carriers and in NC ( p = 0.033 and p < 0.0001, respectively), and demonstrated a trend in LRRK2 G2019S carriers ( p = 0.054), with similar effect sizes (OR = 1.55, 1.62, and 1.49, respectively). PRS association with PD risk in LRRK2 was primarily driven by the rs7938782-A risk allele, replicated in AMP-PD (268 AJs LRRK2 G2019S carriers). PRS and age-at-onset were negatively correlated in NC ( p < 0.0001). NBA GBA1 genotype calls failed at GBA1 L483P and c.115 + 1G > A mutations. False negative call rate of 10.2% was observed for the imputed GBA1 N409S carriers., Conclusions: PRS contributes to PD risk across different genotypes. The genetic and epigenetic role of rs7938782 in LRRK2 PD risk should be further explored. Future PRS models should be tailored to specific genotypes to better understand penetrance and phenotypes. Furthermore, models predicting PD defined biologically rather than clinically may further identify genetic risk factors for synucleinopathies., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2025
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50. GenoTools: an open-source Python package for efficient genotype data quality control and analysis.
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Vitale D, Koretsky MJ, Kuznetsov N, Hong S, Martin J, James M, Makarious MB, Leonard H, Iwaki H, Faghri F, Blauwendraat C, Singleton AB, Song Y, Levine K, Kumar-Sreelatha AA, Fang ZH, and Nalls M
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- Humans, Alzheimer Disease genetics, Parkinson Disease genetics, Genetics, Population, Computational Biology methods, Software, Genotype, Genome-Wide Association Study methods, Quality Control
- Abstract
GenoTools, a Python package, streamlines population genetics research by integrating ancestry estimation, quality control, and genome-wide association studies capabilities into efficient pipelines. By tracking samples, variants, and quality-specific measures throughout fully customizable pipelines, users can easily manage genetics data for large and small studies. GenoTools' "Ancestry" module renders highly accurate predictions, allowing for high-quality ancestry-specific studies, and enables custom ancestry model training and serialization specified to the user's genotyping or sequencing platform. As the genotype processing engine that powers several large initiatives, including the NIH's Center for Alzheimer's and Related Dementias and the Global Parkinson's Genetics Program, GenoTools was used to process and analyze the UK Biobank and major Alzheimer's disease and Parkinson's disease datasets with over 400,000 genotypes from arrays and 5,000 whole genome sequencing samples and has led to novel discoveries in diverse populations. It has provided replicable ancestry predictions, implemented rigorous quality control, and conducted genetic ancestry-specific genome-wide association studies to identify systematic errors or biases through a single command. GenoTools is a customizable tool that enables users to efficiently analyze and scale genotyping and sequencing (whole genome sequencing and exome) data with reproducible and scalable ancestry, quality control, and genome-wide association studies pipelines., Competing Interests: Conflicts of interest: DV, HL, HI, FF, KL, and MN participated in this project in a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. MN also serves on the scientific advisory board for Character Bio Inc., is a scientific founder at Neuron23 Inc., and owns stock., (Published by Oxford University Press on behalf of The Genetics Society of America 2024.)
- Published
- 2025
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