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1. Author Correction: Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Author: Muñoz-Delgado, Laura, Macías-García, Daniel, Periñán, María Teresa, Jesús, Silvia, Adarmes-Gómez, Astrid D., Bonilla Toribio, Marta, Buiza Rueda, Dolores, Jiménez-Jaraba, María del Valle, Benítez Zamora, Belén, Díaz Belloso, Rafael, García-Díaz, Sergio, Martín-Bórnez, Miguel, Pineda Sánchez, Rocío, Carrillo, Fátima, Gómez-Garre, Pilar, and Mir, Pablo
Published: 2023
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2. Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease

Author: Muñoz-Delgado, Laura, Macías-García, Daniel, Periñán, María Teresa, Jesús, Silvia, Adarmes-Gómez, Astrid D., Bonilla Toribio, Marta, Buiza Rueda, Dolores, Jiménez-Jaraba, María del Valle, Benítez Zamora, Belén, Díaz Belloso, Rafael, García-Díaz, Sergio, Martín-Bórnez, Miguel, Pineda Sánchez, Rocío, Carrillo, Fátima, Gómez-Garre, Pilar, and Mir, Pablo
Published: 2023
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3. Homocysteine levels, genetic background, and cognitive impairment in Parkinson’s disease

Author: Periñán, María Teresa, Macías-García, Daniel, Jesús, Silvia, Martín-Rodríguez, Juan Francisco, Muñoz-Delgado, Laura, Jimenez-Jaraba, Maria Valle, Buiza-Rueda, Dolores, Bonilla-Toribio, Marta, Adarmes-Gómez, Astrid Daniela, Gómez-Garre, Pilar, and Mir, Pablo
Published: 2023
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4. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author: Nalls, Mike A, Blauwendraat, Cornelis, Vallerga, Costanza L, Heilbron, Karl, Bandres-Ciga, Sara, Chang, Diana, Tan, Manuela, Kia, Demis A, Noyce, Alastair J, Xue, Angli, Bras, Jose, Young, Emily, von Coelln, Rainer, Simón-Sánchez, Javier, Schulte, Claudia, Sharma, Manu, Krohn, Lynne, Pihlstrøm, Lasse, Siitonen, Ari, Iwaki, Hirotaka, Leonard, Hampton, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Scholz, Sonja W, Botia, Juan A, Martinez, Maria, Corvol, Jean-Christophe, Lesage, Suzanne, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Majamaa, Kari, Toft, Mathias, Andreassen, Ole A, Bangale, Tushar, Brice, Alexis, Yang, Jian, Gan-Or, Ziv, Gasser, Thomas, Heutink, Peter, Shulman, Joshua M, Wood, Nicholas W, Hinds, David A, Hardy, John A, Morris, Huw R, Gratten, Jacob, Visscher, Peter M, Graham, Robert R, Singleton, Andrew B, Team, 23andMe Research, Consortium, System Genomics of Parkinson's Disease, Consortium, International Parkinson's Disease Genomics, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, and Finkbeiner, Steven
Subjects: Neurosciences, Parkinson's Disease, Brain Disorders, Aging, Biotechnology, Prevention, Genetics, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Databases, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Parkinson Disease, Risk Factors, 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Clinical Sciences, Neurology & Neurosurgery
Abstract: BackgroundGenome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.MethodsWe did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.FindingsBetween Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7).InterpretationThese data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.FundingThe National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).
Published: 2019

5. Role of ATP10B in Parkinson Disease in a cohort from southern Spain

Author: Díaz Belloso, Rafael, primary, Muñoz-Delgado, Laura, additional, Martín-Bornez, Miguel, additional, Ojeda, Elena, additional, Periñán, María Teresa, additional, García-Díaz, Sergio, additional, Bonilla-Toribio, Marta, additional, Buiza-Rueda, Dolores, additional, Pineda Sánchez, Rocío, additional, Jesús, Silvia, additional, Macías-García, Daniel, additional, Adarmes-Gómez, Astrid, additional, Carrillo, Fátima, additional, Mir, Pablo, additional, and Gómez-Garre, Pilar, additional
Published: 2024
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6. The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Author: Bandres‐Ciga, Sara, Saez‐Atienzar, Sara, Bonet‐Ponce, Luis, Billingsley, Kimberley, Vitale, Dan, Blauwendraat, Cornelis, Gibbs, Jesse Raphael, Pihlstrøm, Lasse, Gan‐Or, Ziv, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun‐Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, RņBibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott‐Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean‐Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, SimɃn‐Sȥnchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Van Keuren‐Jensen, Kendall, Shulman, Joshua M, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Alcalay, Roy N, Rouleau, Guy A, Hilten, Jacobus J, Marinus, Johan, Adarmes‐GɃmez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesɐs Alberto Bergareche, Bernal‐Bernal, Inmaculada, Blazquez, Marta, Bonilla‐Toribio, Marta, Botȷa, Juan A, Boungiorno, Marȷa Teresa, Buiza‐Rueda, Dolores, Cȥmara, Ana, Carrillo, Fȥtima, CarriɃn‐Claro, Mario, Cerdan, Debora, ClarimɃn, Jordi, Compta, Yaroslau, Casa, Beatrȷz, Diez‐Fairen, Monica, Dols‐Icardo, Oriol, and Duarte, Jacinto
Subjects: Parkinson's Disease, Human Genome, Genetics, Neurosciences, Brain Disorders, Prevention, Neurodegenerative, Genetic Testing, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Decent Work and Economic Growth, Endocytosis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, International Parkinson's Disease Genomics Consortium, Parkinson's disease, endocytosis, genetic risk, heritability, polygenic risk score, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract: BackgroundPD 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.ObjectivesTo comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD.MethodsLinkage 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.ResultsThe 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.ConclusionsWe 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 identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society.
Published: 2019

7. Smoking is associated with age at disease onset in Parkinson's disease

Author: Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols-Icardo, Oriol, de Fabregues, Oriol, Cartagena, Pilar Sanz, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández-Santiago, Rubén, Fernández, Manel, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria Jose, Gonzalez-Aramburu, Isabel, Gorostidi, Ana, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, López de Munain, Adolfo, Macias-Garcia, Daniel, Martínez-Torres, Irene, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Álvarez-Santullano, Marina Mata, Mínguez-Castellanos, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Periñán, Maria Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Tabernero, Cesar, Tartari, Juan Pablo, Tolosa, Eduard, Valldeoriola, Francesc, Vela, Lydia, Vives, Francisco, Pascual-Sedano, Berta, Hernández-Vara, Jorge, Rolán, Dolores Vilas, Bandrés-Ciga, Sara, Rosas, Irene, Morís, Germán, Coto, Eliecer, Blázquez-Estrada, Marta, Suárez, Esther, García-Fernández, Ciara, Martínez, Carmen, Herrera, Israel Duarte, Pérez-Oliveira, Sergio, Álvarez, Victoria, and Menéndez-González, Manuel
Published: 2022
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8. A geroscience approach for Parkinson’s disease: Conceptual framework and design of PROPAG-AGEING project

Author: Adarmes-Gómez, Astrid, Azevedo, Tiago, Bacalini, Maria Giulia, Baldelli, Luca, Bartoletti-Stella, Anna, Bhatia, Kailash P., Bonilla-Toribio, Marta, Boninsegna, Claudia, Broli, Marcella, Buiza-Rueda, Dolores, Calandra-Buonaura, Giovanna, Capellari, Sabina, Carrión-Claro, Mario, Cilea, Rosalia, Clayton, Robert, Cortelli, Pietro, Molin, Alessandra Dal, De Luca, Silvia, De Massis, Patrizia, Dimitri, Giovanna Maria, Doykov, Ivan, Escuela-Martin, Rocio, Fabbri, Giovanni, Franceschi, Claudio, Gabellini, Anna, Garagnani, Paolo, Giuliani, Cristina, Gómez-Garre, Pilar, Guaraldi, Pietro, Hägg, Sara, Hällqvist, Jenny, Halsband, Claire, Heywood, Wendy, Houlden, Henry, Huertas, Ismae, Jesús, Silvia, Jylhävä, Juulia, Labrador-Espinosa, Miguel A., Licari, Cristina, Liò, Pietro, Luchinat, Claudio, Macias, Daniel, Macrì, Stefania, Magrinelli, Francesca, Rodríguez, Juan Francisco Martín, Delledonne, Massimo, Maturo, Maria Giovanna, Mengozzi, Giacomo, Meoni, Gaia, Mignani, Francesco, Milazzo, Maddalena, Mills, Kevin, Mir, Pablo, Mollenhauer, Brit, Nardini, Christine, Nassetti, Stefania Alessandra, Pedersen, Nancy L., Periñán-Tocino, Maria Teresa, Pirazzini, Chiara, Provini, Federica, Ravaioli, Francesco, Sala, Claudia, Sambati, Luisa, Scaglione, Cesa Lorella Maria, Schade, Sebastian, Schreglmann, Sebastian, Spasov, Simeon, Strom, Stephen, Tejera-Parrado, Cristina, Tenori, Leonardo, Trenkwalder, Claudia, Turano, Paola, Valzania, Franco, Ortega, Rosario Vigo, Williams, Dylan, Xumerle, Luciano, Zago, Elisa, Dal Molin, Alessandra, and Kwiatkowska, Katarzyna Malgorzata
Published: 2021
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9. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Author: Adarmes-Gómez, Astrid D, Aguilar, Miquel, Aitkulova, Akbota, Akhmetzhanov, Vadim, Alcalay, Roy N, Alvarez, Ignacio, Alvarez, Victoria, Bandres-Ciga, Sara, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Billingsley, Kimberley, Blauwendraat, Cornelis, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Bras, Jose, Brice, Alexis, Brockmann, Kathrin, Bubb, Vivien, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Chelban, Viorica, Clarimón, Jordi, Clarke, Carl, Compta, Yaroslau, Cookson, Mark R, Corvol, Jean-Christophe, Craig, David W, Danjou, Fabrice, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Escott-Price, Valentina, Ezquerra, Mario, Faghri, Faraz, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Finkbeiner, Steven, Foltynie, Thomas, Gan-Or, Ziv, Garcia, Ciara, García-Ruiz, Pedro, Gasser, Thomas, Gibbs, J Raphael, Gomez Heredia, Maria Jose, Gómez-Garre, Pilar, González, Manuel Menéndez, Gonzalez-Aramburu, Isabel, Guelfi, Sebastian, Guerreiro, Rita, Hardy, John, Hassin-Baer, Sharon, Hernandez, Dena G, Heutink, Peter, Hoenicka, Janet, Holmans, Peter, Houlden, Henry, Infante, Jon, Iwaki, Hirotaka, Jesús, Silvia, Jimenez-Escrig, Adriano, Kaishybayeva, Gulnaz, Kaiyrzhanov, Rauan, Karimova, Altynay, Kia, Demis A, Kinghorn, Kerri J, Koks, Sulev, Krohn, Lynne, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Leonard, Hampton L, Lesage, Suzanne, Lewis, Patrick, Lopez-Sendon, Jose Luis, Lovering, Ruth, Lubbe, Steven, Lungu, Codrin, Macias, Daniel, Majamaa, Kari, Manzoni, Claudia, Marín, Juan, Marinus, Johan, Marti, Maria Jose, Martinez, Maria, Martínez Torres, Irene, Martínez-Castrillo, Juan Carlos, Mata, Marina, Mencacci, Niccolo E, Méndez-del-Barrio, Carlota, Middlehurst, Ben, Mínguez, Adolfo, Mir, Pablo, Mok, Kin Y, Morris, Huw R, Muñoz, Esteban, Nalls, Mike A, Narendra, Derek, Noyce, Alastair J, Ojo, Oluwadamilola O, Okubadejo, Njideka U, Pagola, Ana Gorostidi, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Pihlstrom, Lasse, Plun-Favreau, Helene, Quinn, John, R'Bibo, Lea, Reed, Xylena, Rezola, Elisabet Mondragon, Rizig, Mie, Rizzu, Patrizia, Robak, Laurie, Rodriguez, Antonio Sanchez, Rouleau, Guy A, Ruiz-Martínez, Javier, Ruz, Clara, Ryten, Mina, Sadykova, Dinara, Scholz, Sonja W, Schreglmann, Sebastian, Schulte, Claudia, Sharma, Manu, Shashkin, Chingiz, Shulman, Joshua M, Sierra, María, Siitonen, Ari, Simón-Sánchez, Javier, Singleton, Andrew B, Suarez-Sanmartin, Esther, Taba, Pille, Tabernero, Cesar, Tan, Manuela X, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Toft, Mathias, Tolosa, Eduard, Trabzuni, Daniah, Valldeoriola, Francesc, van Hilten, Jacobus J, Van Keuren-Jensen, Kendall, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Williams, Nigel, Wood, Nicholas W, Zharkinbekova, Nazira, Zharmukhanov, Zharkyn, Zholdybayeva, Elena, Zimprich, Alexander, Ylikotila, Pauli, Shulman, Lisa M., von Coelln, Rainer, Reich, Stephen, Savitt, Joseph, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Huber, Karen E., Hicks, Barry, Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A.M., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce, Vacic, Vladimir, Wang, Xin, Wilson, Catherine H., Anderson, Tim, Bentley, Steven, Dalrymple-Alford, John, Fowdar, Javed, Gratten, Jacob, Halliday, Glenda, Henders, Anjali K., Hickie, Ian, Kassam, Irfahan, Kennedy, Martin, Kwok, John, Lewis, Simon, Mellick, George, Montgomery, Grant, Pearson, John, Pitcher, Toni, Sidorenko, Julia, Silburn, Peter A., Vallerga, Costanza L., Visscher, Peter M., Wallace, Leanne, Wray, Naomi R., Xue, Angli, Yang, Jian, Zhang, Futao, Vallerga, Costanza L, Heilbron, Karl, Chang, Diana, Tan, Manuela, Young, Emily, Pihlstrøm, Lasse, Leonard, Hampton, Botia, Juan A, Jankovic, Joseph, Shulman, Lisa M, Sutherland, Margaret, Tienari, Pentti, Andreassen, Ole A, Bangale, Tushar, Hinds, David A, Hardy, John A, Visscher, Peter M, and Graham, Robert R
Published: 2019
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10. A genetic analysis of a Spanish population with early onset Parkinson's disease.

Author: Tejera-Parrado Cristina, Mir Pablo, Periñán María Teresa, Vela-Desojo Lydia, Abreu-Rodríguez Irene, Alonso-Cánovas Araceli, Bernal-Bernal Inmaculada, Bonilla-Toribio Marta, Buiza-Rueda Dolores, Catalán-Alonso María José, García-Ramos Rocío, García-Ruiz Pedro José, Huertas-Fernández Ismael, Jesús Silvia, Miguel A-Espinosa Labrador, López-Manzanares Lydia, Martínez-Castrillo Juan Carlos, Ignacio J Posada, Rojo-Sebastián Ana, Ruiz-Huete Cristina, Del Val Javier, and Pilar Gómez-Garre
Subjects: Medicine, Science
Abstract: IntroductionBoth recessive and dominant genetic forms of Parkinson's disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson's disease in a cohort from central Spain.Methods/patientsWe analyzed a cohort of 117 unrelated patients with early onset Parkinson's disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson's disease and other Parkinsonisms and CNV screening.ResultsTwenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes.ConclusionsOur results contribute to the understanding of the genetic architecture associated with early onset Parkinson's disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson's disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson's disease.
Published: 2020
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11. Homocysteine levels, genetic background, and cognitive impairment in Parkinson’s disease

Author: Periñán, María Teresa, primary, Macías-García, Daniel, additional, Jesús, Silvia, additional, Martín-Rodríguez, Juan Francisco, additional, Muñoz-Delgado, Laura, additional, Jimenez-Jaraba, Maria Valle, additional, Buiza-Rueda, Dolores, additional, Bonilla-Toribio, Marta, additional, Adarmes-Gómez, Astrid Daniela, additional, Gómez-Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2022
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12. Reply to: “Increased Stroke Risk in Patients with Parkinson's Disease with LRRK2 Mutations”

Author: Macías‐García, Daniel, primary, Periñán, María Teresa, additional, Muñoz‐Delgado, Laura, additional, Jesús, Silvia, additional, Jimenez‐Jaraba, María Valle, additional, Buiza‐Rueda, Dolores, additional, Bonilla‐Toribio, Marta, additional, Adarmes‐Gómez, Astrid, additional, Carrillo, Fátima, additional, Gómez‐Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2022
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13. Smoking is associated with age at disease onset in Parkinson's disease

Author: Rosas, Irene, primary, Morís, Germán, additional, Coto, Eliecer, additional, Blázquez-Estrada, Marta, additional, Suárez, Esther, additional, García-Fernández, Ciara, additional, Martínez, Carmen, additional, Herrera, Israel Duarte, additional, Pérez-Oliveira, Sergio, additional, Álvarez, Victoria, additional, Menéndez-González, Manuel, additional, Adarmes-Gómez, Astrid D., additional, Aguilar, Miquel, additional, Alvarez, Ignacio, additional, Barrero, Francisco Javier, additional, Bergareche Yarza, Jesús Alberto, additional, Bonilla-Toribio, Marta, additional, Botía, Juan A., additional, Boungiorno, María Teresa, additional, Buiza-Rueda, Dolores, additional, Cámara, Ana, additional, Carrillo, Fátima, additional, Cerdan, Debora, additional, Clarimón, Jordi, additional, Compta, Yaroslau, additional, Diez-Fairen, Monica, additional, Dols-Icardo, Oriol, additional, de Fabregues, Oriol, additional, Cartagena, Pilar Sanz, additional, Duarte, Jacinto, additional, Duran, Raquel, additional, Escamilla-Sevilla, Francisco, additional, Ezquerra, Mario, additional, Feliz, Cici, additional, Fernández-Santiago, Rubén, additional, Fernández, Manel, additional, García-Ruiz, Pedro, additional, Gómez-Garre, Pilar, additional, Gomez Heredia, Maria Jose, additional, Gonzalez-Aramburu, Isabel, additional, Gorostidi, Ana, additional, Hoenicka, Janet, additional, Infante, Jon, additional, Jesús, Silvia, additional, Jimenez-Escrig, Adriano, additional, Kulisevsky, Jaime, additional, Labrador-Espinosa, Miguel A., additional, Lopez-Sendon, Jose Luis, additional, López de Munain, Adolfo, additional, Macias-Garcia, Daniel, additional, Martínez-Torres, Irene, additional, Marín, Juan, additional, Marti, Maria Jose, additional, Martínez-Castrillo, Juan Carlos, additional, Álvarez-Santullano, Marina Mata, additional, Mínguez-Castellanos, Adolfo, additional, Mir, Pablo, additional, Rezola, Elisabet Mondragon, additional, Muñoz, Esteban, additional, Pagonabarraga, Javier, additional, Pastor, Pau, additional, Errazquin, Francisco Perez, additional, Periñán, Maria Teresa, additional, Ruiz-Martínez, Javier, additional, Ruz, Clara, additional, Rodriguez, Antonio Sanchez, additional, Sierra, María, additional, Tabernero, Cesar, additional, Tartari, Juan Pablo, additional, Tolosa, Eduard, additional, Valldeoriola, Francesc, additional, Vela, Lydia, additional, Vives, Francisco, additional, Pascual-Sedano, Berta, additional, Hernández-Vara, Jorge, additional, Rolán, Dolores Vilas, additional, and Bandrés-Ciga, Sara, additional
Published: 2022
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14. Metabolite and lipoprotein profiles reveal sex-related oxidative stress imbalance in de novo drug-naive Parkinson's disease patients

Author: Meoni, Gaia, Tenori, Leonardo, Schade, Sebastian, Licari, Cristina, Pirazzini, Chiara, Bacalini, Maria Giulia, Garagnani, Paolo, Turano, Paola, Baldelli, Luca, Jesús, Silvia, Schreglmann, Sebastian R, Sambati, Luisa, Gómez-Garre, Pilar, Halsband, Claire, Calandra-Buonaura, Giovanna, Adarmes-Gómez, Astrid Daniela, Sixel-Döring, Friederike, Zenesini, Corrado, Bhatia, Kailash P., Cortelli, Pietro, Mollenhauer, Brit, Franceschi, Claudio, Houlden, Henry, Liò, Pietro, Luchinat, Claudio, Delledonne, Massimo, Mills, Kevin, Pedersen, Nancy L., Azevedo, Tiago, Bartoletti-Stella, Anna, Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Capellari, Sabina, Carriòn-Claro, Mario, Clayton, Robert, Dal Molin, Alessandra, Dimitri, Giovanna Maria, Doykov, Ivan, Giuliani, Cristina, Hägg, Sara, Hällqvist, Jenny, Heywood, Wendy, Huertas, Ismael, Jylhävä, Juulia, Labrador-Espinosa, Miguel A., Macias, Daniel, Magrinelli, Francesca, Rodríguez, Juan Francisco Martín, Maturo, Maria Giovanna, Mengozzi, Giacomo, Milazzo, Maddalena, Nardini, Christine, Periñán-Tocino, Maria Teresa, Ravaioli, Francesco, Sala, Claudia, Spasov, Simeon, Tejera-Parrado, Cristina, Paola, Turano, Williams, Dylan, Xumerle, Luciano, Trenkwalder, Claudia, European Commission, Meoni, Gaia, Tenori, Leonardo, Schade, Sebastian, Turano, Paola, Licari, Cristina, Pirazzini, Chiara, Bacalini, Maria Giulia, Garagnani, Paolo, PROPAG-AGEING Consortium[.., Giuliani, Cristina, Provini, Federica, Calandra Buonaura, Giovanna, Cortelli, Pietro, Capellari, Sabina, ], Trenkwalder, Claudia, Franceschi, Claudio, Mollenhauer, Brit, Luchinat, Claudio, [Meoni, Gaia] Univ Florence, Magnet Resonance Ctr CERM, Florence, Italy, [Tenori, Leonardo] Univ Florence, Magnet Resonance Ctr CERM, Florence, Italy, [Licari, Cristina] Univ Florence, Magnet Resonance Ctr CERM, Florence, Italy, [Turano, Paola] Univ Florence, Magnet Resonance Ctr CERM, Florence, Italy, [Luchinat, Claudio] Univ Florence, Magnet Resonance Ctr CERM, Florence, Italy, [Meoni, Gaia] Univ Florence, Dept Chem Ugo Schiff, Florence, Italy, [Tenori, Leonardo] Univ Florence, Dept Chem Ugo Schiff, Florence, Italy, [Licari, Cristina] Univ Florence, Dept Chem Ugo Schiff, Florence, Italy, [Turano, Paola] Univ Florence, Dept Chem Ugo Schiff, Florence, Italy, [Luchinat, Claudio] Univ Florence, Dept Chem Ugo Schiff, Florence, Italy, [Tenori, Leonardo] Consorzio Interuniv Risonanze Magnet Met Prot CIR, Florence, Italy, [Turano, Paola] Consorzio Interuniv Risonanze Magnet Met Prot CIR, Florence, Italy, [Luchinat, Claudio] Consorzio Interuniv Risonanze Magnet Met Prot CIR, Florence, Italy, [Schade, Sebastian] Univ Med Ctr Goettingen, Dept Clin Neurophysiol, Gottingen, Germany, [Pirazzini, Chiara] IRCCS Ist Sci Neurol Bologna, Bologna, Italy, [Bacalini, Maria Giulia] IRCCS Ist Sci Neurol Bologna, Bologna, Italy, [Garagnani, Paolo] Univ Bologna, Dept Expt Diagnost & Specialty Med DIMES, Bologna, Italy, [Franceschi, Claudio] Univ Bologna, Dept Expt Diagnost & Specialty Med DIMES, Bologna, Italy, [Trenkwalder, Claudia] Univ Med Ctr Goettingen, Dept Neurol & Paracelsus Elena Klin, Kassel, Germany, [Mollenhauer, Brit] Univ Med Ctr Goettingen, Dept Neurol & Paracelsus Elena Klin, Kassel, Germany, [Franceschi, Claudio] Lobachevsky Univ, Lab Syst Med Hlth Aging, Nizhnii Novgorod, Russia, [Franceschi, Claudio] Lobachevsky Univ, Dept Appl Math, Nizhnii Novgorod, Russia, Instruct-ERIC, a Landmark ESFRI project, CERM/CIRMMP Italy Centre, Horizon 2020 Framework Programme (PROPAG-AGEING), Meoni, Gaia [0000-0002-8608-4641], Tenori, Leonardo [0000-0001-6438-059X], Schade, Sebastian [0000-0002-6316-6804], Turano, Paola [0000-0002-7683-8614], Franceschi, Claudio [0000-0001-9841-6386], Luchinat, Claudio [0000-0003-2271-8921], and Apollo - University of Cambridge Repository
Subjects: Risk, Metabolites, ipoproteins, sex-related, oxidative stress imbalance, Parkinson’s disease, NMR, Parkinson's disease, Serum-cholesterol, Predictive markers, Levodopa, Cellular and Molecular Neuroscience, Plasma, RC346-429, Homocysteine, Cholesterol levels, PROPAG-AGEING Consortium, Diagnostic markers, metabolomics, Nmr, Phenotypes, Neurology, PD, Neurology. Diseases of the nervous system, Neurology (clinical), Biomarkers
Abstract: Parkinson's disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress., This work was supported by the Horizon 2020 Framework Programme (grant number 634821, PROPAG-AGEING).
Published: 2022

15. Increased Stroke Risk in Patients with Parkinson’s Disease with LRRK2 Mutations

Author: Macías-García, Daniel, Periñán Tocino, María Teresa, Muñoz Delgado, Laura, Jesús, Silvia, Jiménez Jaraba, María Valle, Buiza Rueda, Dolores, Bonilla Toribio, Marta, Adarmes-Gómez, Astrid, Carrillo, Fátima, Gómez Garre, Pilar, Mir Rivera, Pablo, Universidad de Sevilla. Departamento de Medicina, and Universidad de Sevilla. CTS630: Trastornos del movimiento.
Subjects: LRRK2 Mutations, Stroke Risk, Parkinson’s disease
Abstract: Parkinson’s disease (PD) is associated with an increasedstroke risk, however, no relationship between coronary arterydisease (CAD) and PD was found.1To date, little is knownabout the influence of PD-related genes, such as the leucine-rich repeat kinase 2 (LRRK2), the parkin (PRKN) and theglucocerebrosidase (GBA) genes, in the vascular risk of thesepatients. This work aims to determine whether the vascularrisk differs between sporadic/familial PD forms and controls.
Published: 2022

16. Increased Stroke Risk in Patients with Parkinson's Disease withLRRK2Mutations

Author: Macías‐García, Daniel, primary, Periñán, María Teresa, additional, Muñoz‐Delgado, Laura, additional, Jesús, Silvia, additional, Jimenez‐Jaraba, María Valle, additional, Buiza‐Rueda, Dolores, additional, Bonilla‐Toribio, Marta, additional, Adarmes‐Gómez, Astrid, additional, Carrillo, Fátima, additional, Gómez‐Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2021
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17. Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Author: Baldelli, Luca, Schade, Sebastian, Jesús, Silvia, Schreglmann, Sebastian R., Sambati, Luisa, Gómez-Garre, Pilar, Halsband, Claire, Calandra-Buonaura, Giovanna, Adarmes-Gómez, Astrid Daniela, Sixel-Döring, Friederike, Zenesini, Corrado, Pirazzini, Chiara, Garagnani, Paolo, Bacalini, Maria Giulia, Bhatia, Kailash P., Cortelli, Pietro, Mollenhauer, Brit, Franceschi, Claudio, Mir, Pablo, Trenkwalder, Claudia, Provini, Federica, Houlden, Henry, Liò, Pietro, Luchinat, Claudio, Delledonne, Massimo, Mills, Kevin, Pedersen, Nancy L., Azevedo, Tiago, Bartoletti-Stella, Anna, Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Capellari, Sabina, Carriòn-Claro, Mario, Clayton, Robert, Dal Molin, Alessandra, Dimitri, Giovanna Maria, Doykov, Ivan, Giuliani, Cristina, Hägg, Sara, Hällqvist, Jenny, Heywood, Wendy, Huertas, Ismael, Jylhävä, Juulia, Labrador-Espinosa, Miguel A., Licari, Cristina, Macias, Daniel, Magrinelli, Francesca, Rodríguez, Juan Francisco Martín, Maturo, Maria Giovanna, Mengozzi, Giacomo, Meoni, Gaia, Milazzo, Maddalena, Nardini, Christine, Periñán-Tocino, Maria Teresa, Ravaioli, Francesco, Sala, Claudia, Spasov, Simeon, Tejera-Parrado, Cristina, Tenori, Leonardo, Paola, Turano, Williams, Dylan, Xumerle, Luciano, Zago, Elisa, Broli, Marcella, De Massis, Patrizia, Escuela-Martin, Rocio, Fabbri, Giovanni, Gabellini, Anna, Guaraldi, Pietro, Macrì, Stefania, Nassetti, Stefania Alessandra, Scaglione, Cesa Lorella Maria, Valzania, Franco, Rosaria, Cilea, Mignani, Francesco, Ortega, Rosario Vigo, Boninsegna, Claudia, De Luca, Silvia, Schade, Sebastian [0000-0002-6316-6804], Gómez-Garre, Pilar [0000-0002-0437-6182], Mir, Pablo [0000-0003-1656-302X], Provini, Federica [0000-0001-9063-2658], and Apollo - University of Cambridge Repository
Subjects: 692/617/375/1718, 692/53/2423, article, 692/499
Abstract: A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had
Published: 2021

18. Identification of candidate parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Author: Kia, Demis A., Zhang, David, Guelfi, Sebastian, Manzoni, Claudia, Hubbard, Leon, Reynolds, Regina H., Botía, Juan, Ryten, Mina, Ferrari, Raffaele, Lewis, Patrick A., Williams, Nigel, Trabzuni, Daniah, Hardy, John, Wood, Nicholas W., Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helene, Holmans, Peter, Bras, Jose, PhD, John Quinn, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Rizig, Mie, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Faghri, Faraz, Gibbs, J. Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Ziv, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Javier Barrero, Francisco, Bergareche Yarza, Jesús A., Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María T., Buiza-Rueda, Dolores, Càmara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernàndez, Manel, Fernàndez-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria J., Gonzalez-Aramburu, Isabel, Pagola, Ana G., Hoenicka, Janet, Infante, Jon, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, Arregui, Adolfo López de Munain, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Mèndez-del-Barrio, Carlota, González, Manuel Menéndez, Adolfo Mínguez, Marina Mata, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Perinán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Weale, Michael, Ramasamy, Adaikalavan, Smith, Colin, Guelfi, Manuel Sebastian, D'sa, Karishma, Forabosco, Paola, Botiá, Juan A., and Universidad de Cantabria
Subjects: Candidate gene, Protein catabolic process, Gene Expression, Genome-wide association study, Computational biology, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Databases, Genetic, Humans, Online First, 030212 general & internal medicine, Epigenetics, Gene, Genetic Association Studies, Genetic association, Original Investigation, Research, Parkinson Disease, Protein ubiquitination, Neurology (clinical), Candidate Disease Gene, 030217 neurology & neurosurgery, Comments, Genome-Wide Association Study
Abstract: Key Points Question What genes and genomic processes underlie risk of sporadic Parkinson disease? Findings This genetic association study integrated Parkinson disease genome-wide association study data and brain-derived gene regulation data using various complementary bioinformatic tools and identified 11 candidate genes with evidence of disease-associated regulatory changes. Coexpression and protein level analyses of these genes demonstrated a significant functional association with known mendelian Parkinson disease genes. Meaning This study suggests that gene regulation data may be used to identify candidate genes and pathways involved in sporadic Parkinson disease., Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies., This genetic association study investigates what genes and genomic processes underlie the risk of sporadic Parkinson disease.
Published: 2021

19. GDNF gene is associated with tourette syndrome in a family study

Author: Huertas-Fernández, Ismael, Gómez-Garre, Pilar, Madruga-Garrido, Marcos, Bernal-Bernal, Inmaculada, Bonilla-Toribio, Marta, Martín-Rodríguez, Juan Francisco, Cáceres-Redondo, María Teresa, Vargas-González, Laura, Carrillo, Fátima, Pascual, Alberto, Tischfield, Jay A., King, Robert A., Heiman, Gary A., and Mir, Pablo
Published: 2015
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20. Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Author: Chen, Z., Zhang, D., Reynolds, R.H., Gustavsson, E.K., García-Ruiz, S., D'Sa, K., Fairbrother-Browne, A., Vandrovcova, J., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Morris, H.R., Plun-Favreau, H., Holmans, P., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, Rita, Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Brice, A., Danjou, F., Lesage, S., Corvol, Jean-Christophe, Martinez, M., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M. R, Bandres-Ciga, S., Blauwendraat, Cornelis, Craig, David W, Faghri, F., Gibbs, J.R., Hernandez, D.G., Van Keuren-Jensen, K., Shulman, J.M., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Singleton, A. B., Scholz, S.W., Reed, X., Alcalay, Roy N, Gan-Or, Z., Rouleau, G.A., Krohn, L., van Hilten, J.J., Marinus, J., Adarmes-Gómez, A.D, Aguilar Barberà, Miquel, Alvarez, Ignacio, Alvarez, V., Barrero, F. J, Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, Marta, Botía, J., Boungiorno, M.T., Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, F., Carrión-Claro, M., Cerdan, D., Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, M., Dols Icardo, Oriol, Duarte, J., Duran, Raquel, 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, Miguel 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 Mora, Javier, 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, Alexander, Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Hardy, J., Houlden, Henry, Gagliano Taliun, S. A., Ryten, M., Universitat Autònoma de Barcelona, Universidad de Cantabria, Lord Leonard and Lady Estelle Wolfson Foundation, Medical Research Council (UK), Dementia Research Institute (UK), Alzheimer Society, Alzheimer's Research UK, Wellcome Trust, Dolby Family Fund, National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Agencia Estatal de Investigación (España), Fundación Séneca, and Gobierno de la Región de Murcia
Subjects: 0301 basic medicine, Apolipoprotein E, Aging, Messenger, General Physics and Astronomy, Neurodegenerative, Alzheimer's Disease, Genome, Linkage Disequilibrium, Negative selection, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, health care economics and organizations, Conserved Sequence, Phylogeny, Multidisciplinary, Brain, Neurodegenerative Diseases, Single Nucleotide, Alzheimer's disease, Phenotype, International Parkinson’s Disease Genomics Consortium, Neurological, Regression Analysis, Long Noncoding, DNA, Intergenic, RNA, Long Noncoding, Human, Biotechnology, Lineage (genetic), Science, 1.1 Normal biological development and functioning, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Chromosomes, 03 medical and health sciences, Apolipoproteins E, Underpinning research, Alzheimer Disease, Genetic variation, Genetics, Acquired Cognitive Impairment, Humans, RNA, Messenger, Polymorphism, Gene, Whole genome sequencing, Intergenic, Pair 19, Genome, Human, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Molecular Sequence Annotation, General Chemistry, DNA, Introns, Brain Disorders, 030104 developmental biology, Gene Ontology, RNA, Dementia, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract: Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease., Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.
Published: 2021

21. Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

Author: Blauwendraat, Cornelis, Iwaki, Hirotaka, Gibbs, Jesse R, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Troycoco, Timothy, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Reed, Xylena, Hernandez, Dena Michelle Godwin, Uitti, Ryan J, Ross, Owen A, Grenn, Francis P, Moore, Anni, Alcalay, Roy N, Wszolek, Zbigniew K, Gan-Or, Ziv, Rouleau, Guy A, Krohn, Lynne, Mufti, Kheireddin, Ruskey, Jennifer A, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Blazquez, Marta, Pihlstrøm, Lasse, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Toft, Mathias, Diez-Fairen, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Heredia, Maria Jose Gomez, Gonzalez-Aramburu, Isabel, Pagola, Ana Gorostidi, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A, Lopez-Sendon, Jose Luis, de Munain Arregui, Adolfo López, Macias, Daniel, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-Del-Barrio, Carlota, González, Manuel Menéndez, Schulte, Claudia, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Errazquin, Francisco Perez, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Brockmann, Kathrin, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Sharma, Manu, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Taba, Pille, Koks, Sulev, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Makarious, Mary B, Tienari, Pentti, Okubadejo, Njideka U, Ojo, Oluwadamilola O, Kaiyrzhanov, Rauan, Shashkin, Chingiz, Zharkinbekova, Nazira, Akhmetzhanov, Vadim, Kaishybayeva, Gulnaz, Karimova, Altynay, Khaibullin, Talgat, Lynch, Timothy L, Eerola-Rautio, Johanna, Tienari, Pentti J, Grosset, Donald G, Lesage, Suzanne, Corvol, Jean-Christophe, Brice, Alexis, Wood, Nick, Hardy, John, Bandres-Ciga, Sara, Heutink, Peter, Gasser, Thomas, Morris, Huw R, Noyce, Alastair J, Nalls, Mike A, Consortium, and the International Parkinson's Disease Genomics, Leonard, Hampton L, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Storm, Catherine S, Plun-Favreau, Helene, Holmans, Peter, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y, Kinghorn, Kerri J, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian R, Lovering, Ruth, R'Bibo, Lea, Manzoni, Claudia, Lake, Julie, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Clarke, Carl, Harvey, Kirsten, Jacobs, Benjamin M, Danjou, Fabrice, Martinez, Maria, Simón-Sánchez, Javier, Rizzu, Patrizia, Schneider, Susanne A, Cookson, Mark R, Craig, David W, Billingsley, Kimberley, Kim, Jonggeol J, Narendra, Derek P, Faghri, Faraz, Gibbs, J Raphael, Van Keuren-Jensen, Kendall, Shulman, Joshua M, Robak, Laurie, Universidad de Cantabria, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, University of Helsinki, Clinicum, Research Programs Unit, and Eija Pirinen / Principal Investigator
Subjects: 0301 basic medicine, Male, Genotype, EFFICIENT, Physiology, Genome-wide association study, Disease, Biology, Genetic correlation, 3124 Neurology and psychiatry, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, genetics [Parkinson Disease], Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Parkinson Disease/genetics, METAANALYSIS, Research Articles, Genetic association, Aged, RISK, Sex Characteristics, Autosome, 3112 Neurosciences, Parkinson Disease, Heritability, Middle Aged, Genetic architecture, 3. Good health, 030104 developmental biology, Neurology, Female, GENDER, Neurology (clinical), 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract: 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 13,020male 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 GWASmeta-analyses to identify distinct patterns of genetic risk contributing to disease inmale 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. FUNDING: This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; Project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu – through Germany, BMBF, funding code 01ED1406 and iMed – the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case–Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson’s Network (http://rpq-qpn.ca/en). We thank the Quebec Parkinson’s Network (http://rpq-qpn.org) and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, the full names of all of the PPMI funding partners can be found at www.ppmi-info.org/ fundingpartners. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/ policy. The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript
Published: 2021

22. Identification of sixteen novel candidate genes for late onset Parkinson's disease

Author: Gialluisi, Alessandro, Reccia, Mafalda Giovanna, Modugno, Nicola, Nutile, Teresa, Lombardi, Alessia, Di Giovannantonio, Luca Giovanni, Pietracupa, Sara, Ruggiero, Daniela, Scala, Simona, Gambardella, Stefano, Noyce, Alastair J., Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A., Tan, Manuela, Houlden, Henry, Morris, Huw R., Plun-Favreau, Helen, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Quinn, John, Bubb, Vivien, Mok, Kin Y., Kinghorn, Kerri J., Billingsley, Kimberley, Wood, Nicholas W., Lewis, Patrick, Schreglmann, Sebastian, Lovering, Rruth, R'Bibo, Lea, Manzoni, Claudia, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E., Clarke, Carl, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Cookson, Mark R., Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Narendra, Derek, Faghri, Faraz, Gibbs, J.Raphael, Hernandez, Dena G., Van Keuren-Jensen, Kendall, Shulman, Joshua M., Iwaki, Hirotaka, Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Bras, Jose, Guerreiro, Rita, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B., Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Zin, Rouleau, Guy A., Krohn, Lynne, van Hilten, Jacobus J., Marinus, Johan, Adarmes-Gómez, A.D, Aguilar Barberà, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco Javier, Bergareche Yarza, Jesús Alberto, Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Carrillo, Fátima, Carrión-Claro, M, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, Diez-Fairen, Monica, Dols Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria Jose, Gonzalez-Aramburu, Isabel, Gorostidi Pagola, Ana, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose Luis, López de Munain Arregui, Adolfo, Macias, Daniel, Martínez Torres, Irene, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, Méndez-del-Barrio, Carlota, Menéndez González, Manuel, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Mondragon Rezola, Elisabet, Muñoz, Esteban, Pagonabarraga Mora, Javier, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Sanchez Rodriguez, Antonio, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Majamaa, Kari, Siitonen, Ari, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Shashkin, Chingiz, Zharkynbekova, Nazira, Akhmetzhanov, Vadim, Aitkulova, Akbota, Zholdybayeva, Elena, Zharmukhanov, Zharkyn, Kaishybayeva, Gulnaz, Karimova, Altynay, Sadykova, Dinara, Iacoviello, Licia, Gianfrancesco, F., Acampora, D., D'Esposito, M., Simeone, A., Ciullo, M., Esposito, T., and Universidad de Cantabria
Subjects: 0301 basic medicine, Male, Aging, Candidate gene, Parkinson's disease, Neurodegenerative, Bioinformatics, 0302 clinical medicine, Late onset Parkinson’s disease, Novel candidate genes for Parkinson’s disease, Rare variant burden analysis, Whole exome sequencing, Adult, Age of Onset, Aged, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Parkinson Disease, Pedigree, Whole Exome Sequencing, 2.1 Biological and endogenous factors, Medicine, Novel candidate genes for Parkinson's disease, Aetiology, Exome, Exome sequencing, screening and diagnosis, education.field_of_study, Parkinson's Disease, LRRK2, International Parkinson’s Disease Genomics Consortium, Detection, Neurological, Late onset Parkinson's disease, 4.2 Evaluation of markers and technologies, Research Article, Clinical Sciences, Population, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Exome Sequencing, Genetics, RC346-429, education, Molecular Biology, Neurology & Neurosurgery, business.industry, Genetic heterogeneity, Prevention, RC952-954.6, Neurosciences, PARK7, medicine.disease, Brain Disorders, 030104 developmental biology, Geriatrics, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.
Published: 2021

23. Lack of validation of variants associated with cervical dystonia risk: A GWAS replication study

Author: Gómez-Garre, Pilar, Huertas-Fernández, Ismael, Cáceres-Redondo, María Teresa, Alonso-Canovas, Araceli, Bernal-Bernal, Inmaculada, Blanco-Ollero, Alberto, Bonilla-Toribio, Marta, Burguera, Juan Andrés, Carballo, Manuel, Carrillo, Fatima, Catalán-Alonso, José M., Escamilla-Sevilla, Francisco, Espinosa-Rosso, Raul, Fernández-Moreno, María Carmen, García-Caldentey, Juan, García-Moreno, José Manuel, Giacometti-Silveira, Sandra, Gutiérrez-García, Javier, Jesús-Maestre, Silvia, López-Valdés, Eva, Martínez-Castrillo, Juan Carlos, Medialdea-Natera, María Pilar, Méndez-Lucena, Carolina, Mínguez-Castellanos, Adolfo, Moya, Miguel Angel, Ochoa-Sepulveda, Juan José, Ojea, Tomas, Rodríguez, Nuria, Rubio-Agusti, Ignacio, Sillero-Sánchez, Miriam, del Val, Javier, Vargas-González, Laura, and Mir, Pablo
Published: 2014
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24. Genetic association of sirtuin genes and Parkinson’s disease

Author: Jesús, Silvia, Gómez-Garre, Pilar, Carrillo, Fátima, Cáceres-Redondo, María T., Huertas-Fernández, Ismael, Bernal-Bernal, Inmaculada, Bonilla-Toribio, Marta, Vargas-González, Laura, Carballo, Manuel, and Mir, Pablo
Published: 2013
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25. BDNF Val66Met polymorphism in primary adult-onset dystonia: A case-control study and meta-analysis

Author: Gómez-Garre, Pilar, Huertas-Fernández, Ismael, Cáceres-Redondo, María Teresa, Alonso-Canovas, Araceli, Bernal-Bernal, Inmaculada, Blanco-Ollero, Alberto, Bonilla-Toribio, Marta, Burguera, Juan Andrés, Carballo, Manuel, Carrillo, Fátima, Catalán-Alonso, María José, Escamilla-Sevilla, Francisco, Espinosa-Rosso, Raúl, Fernández-Moreno, María Carmen, García-Caldentey, Juan, García-Moreno, José Manuel, García-Ruiz, Pedro José, Giacometti-Silveira, Sandra, Gutiérrez-García, Javier, Jesús, Silvia, López-Valdés, Eva, Martínez-Castrillo, Juan Carlos, Martínez-Torres, Irene, Medialdea-Natera, María Pilar, Méndez-Lucena, Carolina, Mínguez-Castellanos, Adolfo, Moya, Miguel, Ochoa-Sepulveda, Juan José, Ojea, Tomás, Rodríguez, Nuria, Sillero-Sánchez, Miriam, Vargas-González, Laura, and Mir, Pablo
Published: 2014
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26. A geroscience approach for Parkinson’s disease: Conceptual framework and design of PROPAG-AGEING project

Author: Pirazzini, Chiara, primary, Azevedo, Tiago, additional, Baldelli, Luca, additional, Bartoletti-Stella, Anna, additional, Calandra-Buonaura, Giovanna, additional, Dal Molin, Alessandra, additional, Dimitri, Giovanna Maria, additional, Doykov, Ivan, additional, Gómez-Garre, Pilar, additional, Hägg, Sara, additional, Hällqvist, Jenny, additional, Halsband, Claire, additional, Heywood, Wendy, additional, Jesús, Silvia, additional, Jylhävä, Juulia, additional, Kwiatkowska, Katarzyna Malgorzata, additional, Labrador-Espinosa, Miguel A., additional, Licari, Cristina, additional, Maturo, Maria Giovanna, additional, Mengozzi, Giacomo, additional, Meoni, Gaia, additional, Milazzo, Maddalena, additional, Periñán-Tocino, Maria Teresa, additional, Ravaioli, Francesco, additional, Sala, Claudia, additional, Sambati, Luisa, additional, Schade, Sebastian, additional, Schreglmann, Sebastian, additional, Spasov, Simeon, additional, Tenori, Leonardo, additional, Williams, Dylan, additional, Xumerle, Luciano, additional, Zago, Elisa, additional, Bhatia, Kailash P., additional, Capellari, Sabina, additional, Cortelli, Pietro, additional, Garagnani, Paolo, additional, Houlden, Henry, additional, Liò, Pietro, additional, Luchinat, Claudio, additional, Delledonne, Massimo, additional, Mills, Kevin, additional, Mir, Pablo, additional, Mollenhauer, Brit, additional, Nardini, Christine, additional, Pedersen, Nancy L., additional, Provini, Federica, additional, Strom, Stephen, additional, Trenkwalder, Claudia, additional, Turano, Paola, additional, Bacalini, Maria Giulia, additional, Franceschi, Claudio, additional, Adarmes-Gómez, Astrid, additional, Bonilla-Toribio, Marta, additional, Boninsegna, Claudia, additional, Broli, Marcella, additional, Buiza-Rueda, Dolores, additional, Carrión-Claro, Mario, additional, Cilea, Rosalia, additional, Clayton, Robert, additional, Molin, Alessandra Dal, additional, De Luca, Silvia, additional, De Massis, Patrizia, additional, Escuela-Martin, Rocio, additional, Fabbri, Giovanni, additional, Gabellini, Anna, additional, Giuliani, Cristina, additional, Guaraldi, Pietro, additional, Huertas, Ismae, additional, Macias, Daniel, additional, Macrì, Stefania, additional, Magrinelli, Francesca, additional, Rodríguez, Juan Francisco Martín, additional, Mignani, Francesco, additional, Nassetti, Stefania Alessandra, additional, Pirazzini, Chiara, additional, Scaglione, Cesa Lorella Maria, additional, Tejera-Parrado, Cristina, additional, Valzania, Franco, additional, and Ortega, Rosario Vigo, additional
Published: 2021
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27. A genetic analysis of a Spanish population with early onset Parkinson's disease

Author: Vela-Desojo Lydia, Miguel A. Labrador, Jesús Silvia, Bernal-Bernal Inmaculada, Huertas-Fernández Ismael, Periñán María Teresa, García-Ramos Rocío, Catalán-Alonso María José, Pilar Gómez-Garre, López-Manzanares Lydia, Mir Rivera Pablo, Buiza-Rueda Dolores, Del Val Javier, Ignacio J. Posada, Bonilla-Toribio Marta, Abreu-Rodríguez Irene, García-Ruiz Pedro José, Ruiz-Huete Cristina, Tejera-Parrado Cristina, Martínez-Castrillo Juan Carlos, Alonso-Cánovas Araceli, Rojo-Sebastián Ana, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Universidad de Sevilla
Subjects: 0301 basic medicine, Male, Heredity, Epidemiology, Molecular biology, Disease, Geographical locations, Cohort Studies, Database and Informatics Methods, 0302 clinical medicine, Medical Conditions, Sequencing techniques, Medicine and Health Sciences, DNA sequencing, Age of Onset, Genetics, Multidisciplinary, Movement Disorders, Heterozygosity, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Neurodegenerative Diseases, Parkinson Disease, Genomics, Middle Aged, LRRK2, Europe, Neurology, Medicine, Female, Transcriptome Analysis, Research Article, Next-Generation Sequencing, Adult, Bioinformatics, Science, PINK1, Research and Analysis Methods, 03 medical and health sciences, Genetic variation, medicine, Humans, European Union, Genetic Testing, Genetic testing, Biology and life sciences, business.industry, PARK7, Computational Biology, Correction, Genetic Variation, Human Genetics, Genome Analysis, Human genetics, nervous system diseases, 030104 developmental biology, Molecular biology techniques, Spain, Medical Risk Factors, Genetics of Disease, Age of onset, People and places, business, 030217 neurology & neurosurgery
Abstract: [Introduction] Both recessive and dominant genetic forms of Parkinson’s disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson’s disease in a cohort from central Spain., [Methods/patients] We analyzed a cohort of 117 unrelated patients with early onset Parkinson’s disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson’s disease and other Parkinsonisms and CNV screening., [Results] Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes., [Conclusions] Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson’s disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson’s disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson’s disease., This study was supported by grants from the Spanish Ministry of Economy and Competitiveness [PI14/01823, PI16/01575, PI18/01898] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. Pilar Gómez-Garre was supported by the "Miguel Servet" (from ISCIII-FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programs. Silvia Jesús Maestre was supported by the "Juan Rodés" program (from ISCIII-FEDER). Cristina Tejera was supported by VPPI-US from the Universidad de Sevilla.
Published: 2020

28. The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

Author: Bandres-Ciga, Sara, Ahmed, Sarah, Gómez-Garre, Pilar, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun-Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, PhD, John Quinn, Jesús, Silvia, Mok, Kin Y, Kinghorn, Kerri J, Billingsley, Kimberley, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Manzoni, Claudia, Labrador-Espinosa, Miguel A, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Morrison, Karen E, Brice, Alexis, Danjou, Fabrice, Macias, Daniel, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Méndez-Del-Barrio, Carlota, Nicolas, Aude, Cookson, Mark R, Blauwendraat, Cornelis, Craig, David W, Faghri, Faraz, Gibbs, J Raphael, Hernandez, Dena G, Keuren-Jensen, Kendall Van, Shulman, Joshua M, Periñán-Tocino, Teresa, Iwaki, Hirotaka, Leonard, Hampton L, Nalls, Mike A, Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E, Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W, Tejera-Parrado, Cristina, Reed, Xylena, Alcalay, Roy N, Gan-Or, Ziv, Rouleau, Guy A, Krohn, Lynne, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Aguilar, Miquel, Alvarez, Ignacio, Vargas-González, Laura, Alvarez, Victoria, Barrero, Francisco Javier, Yarza, Jesús Alberto Bergareche, Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A, Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Diez-Fairen, Monica, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Compta, Yaroslau, de la Casa, Beatríz, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubé, Garcia, Ciara, García-Ruiz, Pedro, Heredia, Maria Jose Gomez, Gonzalez-Aramburu, Isabel, Sabir, Marya S, Tartari, Juan Pablo, Pagola, Ana Gorostidi, Hoenicka, Janet, Infante, Jon, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Lopez-Sendon, Jose Luis, Arregui, Adolfo López de Munain, Buongiorno, Mariateresa, Torres, Irene Martínez, Marín, Juan, Marti, Maria Jose, Martínez-Castrillo, Juan Carlos, González, Manuel Menéndez, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Rezola, Elisabet Mondragon, Pagonabarraga, Javier, Pascual-Sedano, Berta, Pastor, Pau, Errazquin, Francisco Perez, Ruiz-Martínez, Javier, Ruz, Clara, Rodriguez, Antonio Sanchez, Sierra, María, Suarez-Sanmartin, Esther, Gorostidi, Ana, Tabernero, Cesar, Tolosa, Eduard, Valldeoriola, Francesc, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Bergareche, Jesús Alberto, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Dalgard, Clifton L, Adeleye, Adelani, Soltis, Anthony R, Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Mondragon, Elisabet, Hupalo, Daniel N, Sukumar, Gauthaman, Pollard, Harvey B, Wilkerson, Matthew D, Martinez, Elisa McGrath, Vinagre-Aragon, Ana, Croitoru, Ioana, Marín-Lahoz, Juan, Fernández-Santiago, Rubén, Muñoz, Esteban, Sanchez Rodriguez, Antonio, Menéndez-González, Manuel, Suarez-San Martin, Esther, Vela-Desojo, Lydia, Mínguez-Castellanos, Adolfo, Gomez Heredia, Maria Jose, Perez Errazquin, Francisco, Romero-Acebal, Manolo, Martínez Torres, Irene, Kim, Jonggeol Jeffrey, Center, American Genome, Brooks, Janet, Saez-Atienzar, Sara, Jorda, Rafael, Botia, Juan A, Bonet-Ponce, Luis, Clarke, Carl, Morris, Huw, Edsall, Connor, Hernandez, Dena, Simon Sanchez, Javier, Marti, Maria José, López de Munain, Adolfo, Singleton, Andrew, Consortium, International Parkinson Disease Genomics, Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, National Institutes of Health (US), Department of Defense (US), Michael J. Fox Foundation for Parkinson's Research, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Junta de Andalucía, Sociedad Andaluza de Neurología, Jacques and Gloria Gossweiler Foundation, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Universidad de Sevilla
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, Parkinson's disease, age at onset, Machine Learning, 0302 clinical medicine, Cost of Illness, genetics [Parkinson Disease], Population specific, genetics [Genetic Predisposition to Disease], Age of Onset, genetics [Ubiquitin-Protein Ligases], Aged, 80 and over, Age at onset, Chromosome Mapping, Parkinson Disease, Middle Aged, Spanish population, humanities, Neurology, Christian ministry, Female, Adult, Genotype, Ubiquitin-Protein Ligases, Article, risk haplotype, 03 medical and health sciences, Risk score risk haplotype, Political science, polygenic risk score, Humans, Genetic Predisposition to Disease, ddc:610, Risk haplotype, Parkinson's disease, Spanish population, age at onset, polygenic risk score, risk haplotype, Aged, DNA Methylation, 030104 developmental biology, Haplotypes, Spain, Case-Control Studies, Polygenic risk score, Neurology (clinical), Polygenic, Humanities, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. Objectives: To perform the largest PD genome-wide association study restricted to a single country. Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain., This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers: 1ZIA‐NS003154‐03, Z01‐AG000949‐02, and Z01‐ES101986). In addition, this work was supported by the Department of Defense (award W81XWH‐09‐2‐0128), The Michael J Fox Foundation for Parkinson's Research, and the ISCIII Grants PI 15/0878 (Fondos Feder) to V.A. and PI 15/01013 to J,H. This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (PI14/01823, PI16/01575, PI18/01898, [SAF2006‐10126 (2006‐2009), SAF2010‐22329‐C02‐01 (2010‐2012), and SAF2013‐47939‐R (2013‐2018)]), co‐founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI‐02526, CTS‐7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI‐0437‐2012, PI‐0471‐2013), the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña. Pilar Gómez‐Garre was supported by the “Miguel Servet” (from ISCIII16 FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programmes. Silvia Jesús Maestre was supported by the “Juan Rodés” programme, and Daniel Macías‐García was supported by the “Río Hortega” programme (both from ISCIII‐FEDER). Cristina Tejera Parrado was supported by VPPI‐US from the Universidad de Sevilla. This research has been conducted using samples from the HUVR‐IBiS Biobank (Andalusian Public Health System Biobank and ISCIII‐Red de Biobancos PT13/0010/0056). This work was also supported by the grant PSI2014‐57643 from the Junta de Andalucía to the CTS‐438 group and a research award from the Andalusian Society of Neurology.
Published: 2019

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

Author: Reynolds, Regina H, Botía, Juan, Gibbs, J Raphael, Duarte, Jacinto, Clarimón, Jordi, Dols-Icardo, Oriol, Infante, Jon, Marín, Juan, Kulisevsky, Jaime, Pagonabarraga, Javier, Gonzalez-Aramburu, Isabel, Rodriguez, Antonio Sanchez, Sierra, María, Hernandez, Dena G, Duran, Raquel, Ruz, Clara, Vives, Francisco, Escamilla-Sevilla, Francisco, Mínguez, Adolfo, Cámara, Ana, Compta, Yaroslau, Ezquerra, Mario, Marti, Maria Jose, Fernández, Manel, Singleton, Andrew B, Muñoz, Esteban, Fernández-Santiago, Rubén, Tolosa, Eduard, Valldeoriola, Francesc, García-Ruiz, Pedro, Heredia, Maria Jose Gomez, Errazquin, Francisco Perez, Hoenicka, Janet, Jimenez-Escrig, Adriano, Martínez-Castrillo, Juan Carlos, Reed, Xylena, Lopez-Sendon, Jose Luis, Torres, Irene Martínez, Tabernero, Cesar, Vela, Lydia, Zimprich, Alexander, Pihlstrom, Lasse, Koks, Sulev, Taba, Pille, Majamaa, Kari, Siitonen, Ari, Leonard, Hampton, Okubadejo, Njideka U, Ojo, Oluwadamilola O, Pitcher, Toni, Anderson, Tim, Bentley, Steven, Fowdar, Javed, Mellick, George, Dalrymple-Alford, John, Henders, Anjali K, Kassam, Irfahan, Blauwendraat, Cornelis, Montgomery, Grant, Sidorenko, Julia, Zhang, Futao, Xue, Angli, Vallerga, Costanza L, Wallace, Leanne, Wray, Naomi R, Yang, Jian, Visscher, Peter M, Gratten, Jacob, Faghri, Faraz, Silburn, Peter A, Halliday, Glenda, Hickie, Ian, Kwok, John, Lewis, Simon, Kennedy, Martin, Pearson, John, Bras, Jose, Guerreiro, Rita, Tucci, Arianna, Nalls, Mike A, Kia, Demis A, Houlden, Henry, Plun-Favreau, Helene, Mok, Kin Y, Wood, Nicholas W, Lovering, Ruth, R'Bibo, Lea, Rizig, Mie, Chelban, Viorica, Trabzuni, Daniah, Hardy, John, Tan, Manuela, Morris, Huw R, Middlehurst, Ben, Quinn, John, Billingsley, Kimberley, Holmans, Peter, Kinghorn, Kerri J, Lewis, Patrick, Escott-Price, Valentina, Williams, Nigel, Gagliano Taliun, Sarah A, Foltynie, Thomas, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Giri, Anamika, Schulte, Claudia, Brockmann, Kathrin, Simon Sanchez, Javier, Ryten, Mina, Heutink, Peter, Gasser, Thomas, Rizzu, Patrizia, Sharma, Manu, Shulman, Joshua M, Robak, Laurie, Lubbe, Steven, Mencacci, Niccolo E, Finkbeiner, Steven, Lungu, Codrin, Noyce, Alastair J, Scholz, Sonja W, Gan-Or, Ziv, Rouleau, Guy A, Krohan, Lynne, van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D, Bernal-Bernal, Inmaculada, Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Nicolas, Aude, Carrillo, Fátima, Carrión-Claro, Mario, Mir, Pablo, Gómez-Garre, Pilar, Jesús, Silvia, Labrador-Espinosa, Miguel A, Macias, Daniel, Vargas-González, Laura, Méndez-Del-Barrio, Carlota, Periñán-Tocino, Teresa, Cookson, Mark R, Tejera-Parrado, Cristina, Diez-Fairen, Monica, Aguilar, Miquel, Alvarez, Ignacio, Boungiorno, María Teresa, Carcel, Maria, Pastor, Pau, Tartari, Juan Pablo, Alvarez, Victoria, González, Manuel Menéndez, Bandres-Ciga, Sara, Blazquez, Marta, Garcia, Ciara, Suarez-Sanmartin, Esther, Barrero, Francisco Javier, Rezola, Elisabet Mondragon, Yarza, Jesús Alberto Bergareche, Pagola, Ana Gorostidi, de Munain Arregui, Adolfo López, Ruiz-Martínez, Javier, and Cerdan, Debora
Subjects: Regulation of gene expression, 0303 health sciences, Cell type, Parkinson's disease, Microglia, Dopaminergic, Genomics, Disease, Biology, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, ddc:610, Neuroscience, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.
Published: 2019

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

Author: Reynolds, R. H., Botía, J., Nalls, M. A., Noyce, A. J., Nicolas, A., Cookson, M. R., Bandres-Ciga, S., Gibbs, J. R., Hernandez, D. G., Singleton, A. B., Reed, X., Leonard, H., Blauwendraat, Cornelis, Faghri, F., Bras, J., Guerreiro, Rita, Tucci, A., Kia, Demis A, Houlden, Henry, Plun-Favreau, H., Mok, K. Y., Wood, N. W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, Viorica, Trabzuni, D., Tan, M., Morris, H. R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, Peter, Kinghorn, K. J., Lewis, P., Escott-Price, Valentina, Williams, N., Foltynie, T., Brice, Alexis, Danjou, F., Lesage, S., Corvol, Jean-Christophe, Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simón-Sánchez, J., Heutink, Peter, Gasser, Thomas, Rizzu, P., Sharma, M., Shulman, J. M., Robak, L., Lubbe, S., Mencacci, N. E., Finkbeiner, S., Lungu, C., Scholz, S. W., Gan-Or, Z., Rouleau, G. A., Krohan, L., van Hilten, J. J., Marinus, J., Adarmes-Gómez, A.D, Bernal-Bernal, I., Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Carrillo, F., Carrión-Claro, M., Mir, P., Gómez-Garre, P., Jesús, S., Labrador-Espinosa, Miguel A, Macías-García, Daniel, Vargas-González, L., Méndez-del-Barrio, C., Periñán-Tocino, T., Tejera-Parrado, C., Diez-Fairen, Monica., Aguilar Barberà, Miquel, Alvarez, Ignacio, Boungiorno, M. T., Carcel, M., Pastor, Pau, Tartari, J. P., Alvarez, V., González, M. M., Blázquez Estrada, Marta, Garcia, C.., Suarez-Sanmartin, E., Barrero, F. J., Rezola, E. M., Yarza, J. A. B., Pagola, A. G., de Munain Arregui, A. L., Ruiz-Martínez, J., Cerdan, Debora, Duarte, J., Clarimón, Jordi, Dols Icardo, Oriol, Infante, J., Marín, J., Kulisevsky, Jaime, Pagonabarraga Mora, Javier, Gonzalez-Aramburu, Isabel, Rodriguez, A. S., Sierra, M., Duran, Raquel, Ruz, C., Vives, F., Escamilla-Sevilla, F., Mínguez, A., Cámara, Ana, Compta, Yaroslau, Ezquerra, M., Marti, M. J., Fernández, M., Muñoz García, José Esteban, Fernández Santiago, Rubén, Tolosa, E., Valldeoriola, F., García-Ruiz, P., Heredia, M. J. G., Errazquin, F. P., Hoenicka, J., Jimenez-Escrig, A., Martínez-Castrillo, J. C., Lopez-Sendon, J. L., Torres, I. M., Tabernero, C., Vela, Lydia, Zimprich, Alexander, Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N. U., Ojo, O. O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, Anjali K, Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F., Xue, A., Vallerga, C. L., Wallace, Leanne, Wray, N. R., Yang, J., Visscher, P. M., Gratten, J., Silburn, P. A., Halliday, G., Hickie, Ian B, Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Hardy, J., Gagliano Taliun, S. A., Ryten, Mina, and Universitat Autònoma de Barcelona
Abstract: Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.
Published: 2019

31. LRP10 in α-synucleinopathies

Author: Kia, Demis A, primary, Sabir, Marya S, additional, Ahmed, Sarah, additional, Trinh, Joanne, additional, Bandres-Ciga, Sara, additional, Noyce, Alastair J, additional, Kaiyrzhanov, Rauan, additional, Middlehurst, Ben, additional, Kia, Demis A, additional, Tan, Manuela, additional, Houlden, Henry, additional, Morris, Huw R, additional, Plun-Favreau, Helene, additional, Holmans, Peter, additional, Hardy, John, additional, Trabzuni, Daniah, additional, Bras, Jose, additional, Quinn, John, additional, Mok, Kin Y, additional, Kinghorn, Kerri J., additional, Billingsley, Kimberley, additional, Wood, Nicholas W, additional, Lewis, Patrick, additional, Schreglmann, Sebastian, additional, Guerreiro, Rita, additional, Lovering, Ruth, additional, R'Bibo, Lea, additional, Rizig, Mie, additional, Ryten, Mina, additional, Guelfi, Sebastian, additional, Escott-Price, Valentina, additional, Chelban, Viorica, additional, Foltynie, Thomas, additional, Williams, Nigel, additional, Brice, Alexis, additional, Danjou, Fabrice, additional, Lesage, Suzanne, additional, Corvol, Jean-Christophe, additional, Martinez, Maria, additional, Schulte, Claudia, additional, Brockmann, Kathrin, additional, Simón-Sánchez, Javier, additional, Heutink, Peter, additional, Rizzu, Patrizia, additional, Sharma, Manu, additional, Gasser, Thomas, additional, Nicolas, Aude, additional, Cookson, Mark R, additional, Blauwendraat, Cornelis, additional, Craig, David W., additional, Faghri, Faraz, additional, Gibbs, Raphael J., additional, Hernandez, Dena G, additional, Van Keuren-Jensen, Kendall, additional, Shulman, Joshua M., additional, Iwaki, Hirotaka, additional, Leonard, Hampton L., additional, Nalls, Mike A., additional, Robak, Laurie, additional, Lubbe, Steven, additional, Finkbeiner, Steven, additional, Mencacci, Niccolo E., additional, Lungu, Codrin, additional, Singleton, Andrew B, additional, Scholz, Sonja W., additional, Reed, Xylena, additional, Alcalay, Roy N., additional, Gan-Or, Ziv, additional, Rouleau, Guy A., additional, van Hilten, Jacobus J, additional, Marinus, Johan, additional, Adarmes-Gómez, Astrid D., additional, Aguilar, Miquel, additional, Alvarez, Ignacio, additional, Alvarez, Victoria, additional, Barrero, Francisco J., additional, Bergareche Yarza, Jesús A., additional, Bernal-Bernal, Inmaculada, additional, Blazquez, Marta, additional, Bonilla-Toribio, Marta, additional, Botía, Juan A., additional, Boungiorno, María Teresa, additional, Buiza-Rueda, Dolores, additional, Cámara, Ana, additional, Carrillo, Fátima, additional, Carrión-Claro, Mario, additional, Cerdan, Debora, additional, Clarimón, Jordi, additional, Diez-Farien, Monica, additional, Dols-Icardo, Oriol, additional, Duarte, Jacinto, additional, Duran, Raquel, additional, Escamilla-Sevilla, Francisco, additional, Ezquerra, Mario, additional, Feliz, Cici, additional, Fernández, Manel, additional, Fernández-Santiago, Rubén, additional, Garcia, Ciara, additional, García-Ruiz, Pedro, additional, Gómez-Garre, Pilar, additional, Gomez Heredia, Maria Jose, additional, Gonzalez-Aramburu, Isabel, additional, Gorostidi Pagola, Ana, additional, Hoenicka, Janet, additional, Infante, Jon, additional, Jesús, Silvia, additional, Jimenez-Escrig, Adriano, additional, Kulisevsky, Jaime, additional, Labrador-Espinosa, Miguel A., additional, Lopez-Sendon, Jose L., additional, López de Munain Arregui, Adolfo, additional, Macias, Daniel, additional, Martínez Torres, Irene, additional, Marín, Juan, additional, Marti, Maria Jose, additional, Martínez- Castrillo, Juan Carlos, additional, Méndez-del-Barrio, Carlota, additional, Menéndez González, Manuel, additional, Mata, Marina, additional, Mínguez, Adolfo, additional, Mir, Pablo, additional, Mondragon Rezola, Elisabet, additional, Muñoz, Esteban, additional, Pagonabarraga, Javier, additional, Pastor, Pau, additional, Perez Errazquin, Francisco, additional, Periñán-Tocino, Teresa, additional, Ruiz-Martínez, Javier, additional, Ruz, Clara, additional, Sanchez Rodriguez, Antonio, additional, Sierra, María, additional, Suarez-Sanmartin, Esther, additional, Tabernero, Cesar, additional, Tartari, Juan Pablo, additional, Tejera-Parrado, Cristina, additional, Tolosa, Eduard, additional, Valldeoriola, Francesc, additional, Vargas-González, Laura, additional, Vela, Lydia, additional, Vives, Francisco, additional, Zimprich, Alexander, additional, Pihlstrom, Lasse, additional, Toft, Mathias, additional, Koks, Sulev, additional, Taba, Pille, additional, and Hassin-Baer, Sharon, additional
Published: 2018
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32. Increased Stroke Risk in Patients with Parkinson's Disease with LRRK2 Mutations.

Author: Macías‐García, Daniel, Periñán, María Teresa, Muñoz‐Delgado, Laura, Jesús, Silvia, Jimenez‐Jaraba, María Valle, Buiza‐Rueda, Dolores, Bonilla‐Toribio, Marta, Adarmes‐Gómez, Astrid, Carrillo, Fátima, Gómez‐Garre, Pilar, and Mir, Pablo
Published: 2022
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33. GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Author: Jesús Maestre, Silvia, Huertas Fernández, Ismael, Bernal Bernal, Inmaculada, Bonilla Toribio, Marta, Cáceres-Redondo, María Teresa, Vargas González, Laura, Calderón Sandubete, Enrique José, Mir Rivera, Pablo, Universidad de Sevilla. Departamento de Medicina, and Universidad de Sevilla. CTS630: Transtornos del movimiento
Subjects: GBA variants, Parkinson’s disease
Abstract: The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying dele- terious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complica- tions could be influenced by GBA variants. Ministerio de Economı́a y Competitividad SAF2007-60700. Instituto de Salud Carlos III PI10/01674, PI13/01461, PI14/01823. Consejerı́a de Economı́a, Innovación, Ciencia y Empleo CVI-02526, CTS- 7685 Consejería de Igualdad, Salud y Políticas Sociales PI-0377/2007, PI-0741/2010, PI-0437-2012, PI-0471-2013
Published: 2016

34. TMEM230 in Parkinson’s disease in a southern Spanish population

Author: Tejera-Parrado, Cristina, primary, Jesús, Silvia, additional, López-Ruíz, Adrián, additional, Buiza-Rueda, Dolores, additional, Bonilla-Toribio, Marta, additional, Bernal-Bernal, Inmaculada, additional, Periñán, María Teresa, additional, Vargas-González, Laura, additional, Gómez-Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2018
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35. Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease

Author: Huertas, Ismael, primary, Jesús, Silvia, additional, García-Gómez, Francisco Javier, additional, Lojo, José Antonio, additional, Bernal-Bernal, Inmaculada, additional, Bonilla-Toribio, Marta, additional, Martín-Rodriguez, Juan Francisco, additional, García-Solís, David, additional, Gómez-Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2017
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36. Genetic analysis of CHCHD2 in a southern Spanish population

Author: Tejera-Parrado, Cristina, primary, Jesús, Silvia, additional, Huertas-Fernández, Ismael, additional, Bernal-Bernal, Inmaculada, additional, Bonilla-Toribio, Marta, additional, Córdoba-Tevar, Isabel, additional, Abreu-Rodríguez, Irene, additional, Carrillo, Fátima, additional, Bernal-Escudero, Maravilla, additional, Vargas-González, Laura, additional, Carballo, Manuel, additional, Gómez-Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2017
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37. GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Author: Jesús, Silvia, primary, Huertas, Ismael, additional, Bernal-Bernal, Inmaculada, additional, Bonilla-Toribio, Marta, additional, Cáceres-Redondo, María Teresa, additional, Vargas-González, Laura, additional, Gómez-Llamas, Myriam, additional, Carrillo, Fátima, additional, Calderón, Enrique, additional, Carballo, Manuel, additional, Gómez-Garre, Pilar, additional, and Mir, Pablo, additional
Published: 2016
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38. LRP10 in α-synucleinopathies

Author: Noyce, Alastair J, Kaiyrzhanov, Rauan, Middlehurst, Ben, Kia, Demis A, Tan, Manuela, Houlden, Henry, Morris, Huw R, Plun-Favreau, Helene, Holmans, Peter, Hardy, John, Trabzuni, Daniah, Bras, Jose, Quinn, John, Mok, Kin Y, Kinghorn, Kerri J., Billingsley, Kimberley, Wood, Nicholas W, Lewis, Patrick, Schreglmann, Sebastian, Guerreiro, Rita, Lovering, Ruth, R'Bibo, Lea, Rizig, Mie, Ryten, Mina, Guelfi, Sebastian, Escott-Price, Valentina, Chelban, Viorica, Foltynie, Thomas, Williams, Nigel, Brice, Alexis, Danjou, Fabrice, Lesage, Suzanne, Corvol, Jean-Christophe, Martinez, Maria, Schulte, Claudia, Brockmann, Kathrin, Simón-Sánchez, Javier, Heutink, Peter, Rizzu, Patrizia, Sharma, Manu, Gasser, Thomas, Nicolas, Aude, Cookson, Mark R, Bandres-Ciga, Sara, Blauwendraat, Cornelis, Craig, David W., Faghri, Faraz, Gibbs, Raphael J., Hernandez, Dena G, Van Keuren-Jensen, Kendall, Shulman, Joshua M., Iwaki, Hirotaka, Leonard, Hampton L., Nalls, Mike A., Robak, Laurie, Lubbe, Steven, Finkbeiner, Steven, Mencacci, Niccolo E., Lungu, Codrin, Singleton, Andrew B, Scholz, Sonja W., Reed, Xylena, Alcalay, Roy N., Gan-Or, Ziv, Rouleau, Guy A., van Hilten, Jacobus J, Marinus, Johan, Adarmes-Gómez, Astrid D., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Barrero, Francisco J., Bergareche Yarza, Jesús A., Bernal-Bernal, Inmaculada, Blazquez, Marta, Bonilla-Toribio, Marta, Botía, Juan A., Boungiorno, María Teresa, Buiza-Rueda, Dolores, Cámara, Ana, Carrillo, Fátima, Carrión-Claro, Mario, Cerdan, Debora, Clarimón, Jordi, Diez-Farien, Monica, Dols-Icardo, Oriol, Duarte, Jacinto, Duran, Raquel, Escamilla-Sevilla, Francisco, Ezquerra, Mario, Feliz, Cici, Fernández, Manel, Fernández-Santiago, Rubén, Garcia, Ciara, García-Ruiz, Pedro, Gómez-Garre, Pilar, Gomez Heredia, Maria Jose, Gonzalez-Aramburu, Isabel, Gorostidi Pagola, Ana, Hoenicka, Janet, Infante, Jon, Jesús, Silvia, Jimenez-Escrig, Adriano, Kulisevsky, Jaime, Labrador-Espinosa, Miguel A., Lopez-Sendon, Jose L., López de Munain Arregui, Adolfo, Macias, Daniel, Martínez Torres, Irene, Marín, Juan, Marti, Maria Jose, Martínez- Castrillo, Juan Carlos, Méndez-del-Barrio, Carlota, Menéndez González, Manuel, Mata, Marina, Mínguez, Adolfo, Mir, Pablo, Mondragon Rezola, Elisabet, Muñoz, Esteban, Pagonabarraga, Javier, Pastor, Pau, Perez Errazquin, Francisco, Periñán-Tocino, Teresa, Ruiz-Martínez, Javier, Ruz, Clara, Sanchez Rodriguez, Antonio, Sierra, María, Suarez-Sanmartin, Esther, Tabernero, Cesar, Tartari, Juan Pablo, Tejera-Parrado, Cristina, Tolosa, Eduard, Valldeoriola, Francesc, Vargas-González, Laura, Vela, Lydia, Vives, Francisco, Zimprich, Alexander, Pihlstrom, Lasse, Toft, Mathias, Koks, Sulev, Taba, Pille, Hassin-Baer, Sharon, Sabir, Marya S, Ahmed, Sarah, and Trinh, Joanne
Published: 2018
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39. Systematic mutational analysis of FBXO7 in a Parkinson's disease population from southern Spain

Author: Gómez-Garre, Pilar, primary, Jesús, Silvia, additional, Carrillo, Fátima, additional, Cáceres-Redondo, Maria Teresa, additional, Huertas-Fernández, Ismael, additional, Bernal-Bernal, Inmaculada, additional, Bonilla-Toribio, Marta, additional, Vargas-González, Laura, additional, Carballo, Manuel, additional, and Mir, Pablo, additional
Published: 2014
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40. Analysis of c.801-2A>G mutation in the DNAJC6 gene in Parkinson's disease in southern Spain

Author: Jesús, Silvia, primary, Gómez-Garre, Pilar, additional, Carrillo, Fátima, additional, Cáceres-Redondo, María T., additional, Huertas-Fernández, Ismael, additional, Bernal-Bernal, Inmaculada, additional, Bonilla-Toribio, Marta, additional, Vargas-González, Laura, additional, Carballo, Manuel, additional, and Mir, Pablo, additional
Published: 2014
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41. The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.

Author: Bandres-Ciga S, Ahmed S, Sabir MS, Blauwendraat C, Adarmes-Gómez AD, Bernal-Bernal I, Bonilla-Toribio M, Buiza-Rueda D, Carrillo F, Carrión-Claro M, Gómez-Garre P, Jesús S, Labrador-Espinosa MA, Macias D, Méndez-Del-Barrio C, Periñán-Tocino T, Tejera-Parrado C, Vargas-González L, Diez-Fairen M, Alvarez I, Tartari JP, Buongiorno M, Aguilar M, Gorostidi A, Bergareche JA, Mondragon E, Vinagre-Aragon A, Croitoru I, Ruiz-Martínez J, Dols-Icardo O, Kulisevsky J, Marín-Lahoz J, Pagonabarraga J, Pascual-Sedano B, Ezquerra M, Cámara A, Compta Y, Fernández M, Fernández-Santiago R, Muñoz E, Tolosa E, Valldeoriola F, Gonzalez-Aramburu I, Sanchez Rodriguez A, Sierra M, Menéndez-González M, Blazquez M, Garcia C, Suarez-San Martin E, García-Ruiz P, Martínez-Castrillo JC, Vela-Desojo L, Ruz C, Barrero FJ, Escamilla-Sevilla F, Mínguez-Castellanos A, Cerdan D, Tabernero C, Gomez Heredia MJ, Perez Errazquin F, Romero-Acebal M, Feliz C, Lopez-Sendon JL, Mata M, Martínez Torres I, Kim JJ, Dalgard CL, Brooks J, Saez-Atienzar S, Gibbs JR, Jorda R, Botia JA, Bonet-Ponce L, Morrison KE, Clarke C, Tan M, Morris H, Edsall C, Hernandez D, Simon-Sanchez J, Nalls MA, Scholz SW, Jimenez-Escrig A, Duarte J, Vives F, Duran R, Hoenicka J, Alvarez V, Infante J, Marti MJ, Clarimón J, López de Munain A, Pastor P, Mir P, and Singleton A
Subjects: Adult, Age of Onset, Aged, Aged, 80 and over, Case-Control Studies, Chromosome Mapping, Cost of Illness, DNA Methylation, Female, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Machine Learning, Male, Middle Aged, Multifactorial Inheritance, Spain, Ubiquitin-Protein Ligases genetics, Parkinson Disease genetics
Abstract: Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases., Objectives: To perform the largest PD genome-wide association study restricted to a single country., Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses., Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls., Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)
Published: 2019
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