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1. A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Author

Yahaira Naaldijk, Belén Fernández, Rachel Fasiczka, Elena Fdez, Coline Leghay, Ioana Croitoru, John B. Kwok, Yanisse Boulesnane, Amelie Vizeneux, Eugenie Mutez, Camille Calvez, Alain Destée, Jean-Marc Taymans, Ana Vinagre Aragon, Alberto Bergareche Yarza, Shalini Padmanabhan, Mario Delgado, Roy N. Alcalay, Zac Chatterton, Nicolas Dzamko, Glenda Halliday, Javier Ruiz-Martínez, Marie-Christine Chartier-Harlin, and Sabine Hilfiker

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

Published
2024
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2. Clinical utility of a personalized and long-term monitoring device for Parkinson's disease in a real clinical practice setting: An expert opinion survey on STAT-ON™

Author

Santos García, D., López Ariztegui, N., Cubo, E., Vinagre Aragón, A., García-Ramos, R., Borrué, C., Fernández-Pajarín, G., Caballol, N., Cabo, I., Barrios-López, J.M., Hernández Vara, J., Ávila Rivera, M.A., Gasca-Salas, C., Escalante, S., Manrique de Lara, P., Pérez Noguera, R., Álvarez Sauco, M., Sierra, M., Monje, M.H.G., Sánchez Ferro, A., Novo Ponte, S., Alonso-Frech, F., Macías-García, D., Legarda, I., Rojo, A., Álvarez Fernández, I., Buongiorno, M.T., Pastor, P., and García Ruíz, P.

Published
2023
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3. Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort

Author

Zhao, Yujia, Lai, Yunjia, Konijnenberg, Hilde, Huerta, José María, Vinagre-Aragon, Ana, Sabin, Jara Anna, Hansen, Johnni, Petrova, Dafina, Sacerdote, Carlotta, Zamora-Ros, Raul, Pala, Valeria, Heath, Alicia K, Panico, Salvatore, Guevara, Marcela, Masala, Giovanna, Lill, Christina M, Miller, Gary W, Peters, Susan, Vermeulen, Roel, Zhao, Yujia, Lai, Yunjia, Konijnenberg, Hilde, Huerta, José María, Vinagre-Aragon, Ana, Sabin, Jara Anna, Hansen, Johnni, Petrova, Dafina, Sacerdote, Carlotta, Zamora-Ros, Raul, Pala, Valeria, Heath, Alicia K, Panico, Salvatore, Guevara, Marcela, Masala, Giovanna, Lill, Christina M, Miller, Gary W, Peters, Susan, and Vermeulen, Roel

Abstract

BACKGROUND AND OBJECTIVES: Inverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD.METHODS: Associations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk.RESULTS: In the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results. DISCUSSION: This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine a

Published
2024

4. Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort

Author

IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Zhao, Yujia, Lai, Yunjia, Konijnenberg, Hilde, Huerta, José María, Vinagre-Aragon, Ana, Sabin, Jara Anna, Hansen, Johnni, Petrova, Dafina, Sacerdote, Carlotta, Zamora-Ros, Raul, Pala, Valeria, Heath, Alicia K, Panico, Salvatore, Guevara, Marcela, Masala, Giovanna, Lill, Christina M, Miller, Gary W, Peters, Susan, Vermeulen, Roel, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Zhao, Yujia, Lai, Yunjia, Konijnenberg, Hilde, Huerta, José María, Vinagre-Aragon, Ana, Sabin, Jara Anna, Hansen, Johnni, Petrova, Dafina, Sacerdote, Carlotta, Zamora-Ros, Raul, Pala, Valeria, Heath, Alicia K, Panico, Salvatore, Guevara, Marcela, Masala, Giovanna, Lill, Christina M, Miller, Gary W, Peters, Susan, and Vermeulen, Roel

Published
2024

5. Prediagnostic Blood Metal Levels and the Risk of Parkinson's Disease: A Large European Prospective Cohort

Author

Zhao, Yujia, Ray, Anushree, Broberg, Karin, Kippler, Maria, Lill, Christina M, Vineis, Paolo, Katzke, Verena A, Rodriguez-Barranco, Miguel, Chirlaque, María-Dolores, Guevara, Marcela, Gómez, Jesús-Humberto, Hansen, Johnni, Panico, Salvatore, Middleton, Lefkos T, Masala, Giovanna, Pala, Valeria, Vinagre-Aragon, Ana, Zibetti, Maurizio, Vermeulen, Roel, Peters, Susan, Zhao, Yujia, Ray, Anushree, Broberg, Karin, Kippler, Maria, Lill, Christina M, Vineis, Paolo, Katzke, Verena A, Rodriguez-Barranco, Miguel, Chirlaque, María-Dolores, Guevara, Marcela, Gómez, Jesús-Humberto, Hansen, Johnni, Panico, Salvatore, Middleton, Lefkos T, Masala, Giovanna, Pala, Valeria, Vinagre-Aragon, Ana, Zibetti, Maurizio, Vermeulen, Roel, and Peters, Susan

Abstract

Background: Metals have been postulated as environmental concerns in the etiology of Parkinson's disease (PD), but metal levels are typically measured after diagnosis, which might be subject to reverse causality. Objective: The aim of this study was to investigate the association between prediagnostic blood metal levels and PD risk. Methods: A case-control study was nested in a prospective European cohort, using erythrocyte samples collected before PD diagnosis. Results: Most assessed metals were not associated with PD risk. Cadmium has a suggestive negative association with PD (odds ratio [95% confidence interval] for the highest quartile, 0.70 [0.42–1.17]), which diminished among never smokers. Among current smokers only, lead was associated with decreased PD risk (0.06 [0.01–0.35]), whereas arsenic showed associations toward an increased PD risk (1.85 [0.45–7.93]). Conclusions: We observe no strong evidence to support a role of metals in the development of PD. In particular, smoking may confound the association with tobacco-derived metals.

Published
2023

6. Prediagnostic Blood Metal Levels and the Risk of Parkinson's Disease: A Large European Prospective Cohort

Author

IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Zhao, Yujia, Ray, Anushree, Broberg, Karin, Kippler, Maria, Lill, Christina M, Vineis, Paolo, Katzke, Verena A, Rodriguez-Barranco, Miguel, Chirlaque, María-Dolores, Guevara, Marcela, Gómez, Jesús-Humberto, Hansen, Johnni, Panico, Salvatore, Middleton, Lefkos T, Masala, Giovanna, Pala, Valeria, Vinagre-Aragon, Ana, Zibetti, Maurizio, Vermeulen, Roel, Peters, Susan, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Zhao, Yujia, Ray, Anushree, Broberg, Karin, Kippler, Maria, Lill, Christina M, Vineis, Paolo, Katzke, Verena A, Rodriguez-Barranco, Miguel, Chirlaque, María-Dolores, Guevara, Marcela, Gómez, Jesús-Humberto, Hansen, Johnni, Panico, Salvatore, Middleton, Lefkos T, Masala, Giovanna, Pala, Valeria, Vinagre-Aragon, Ana, Zibetti, Maurizio, Vermeulen, Roel, and Peters, Susan

Published
2023

7. 20986. ANGIOPATÍA AMILOIDE CEREBRAL EN MENORES DE 55 AÑOS CON HEMORRAGIA INTRAPARENQUIMATOSA EN UNA COHORTE HOSPITALARIA

Author

Albajar Gómez, I., Narraspe, L., de la Riva Juez, P., Núñez Manjarres, G., Marta Enguita, J., Escobar Padilla, A., Lijeron Farel, S., Ayuso García, D., Álvarez Agoues, K., Jauregui Larrañaga, C., de Arce Borda, A., Díez González, N., Pardina Vilella, L., González López, F., Equiza Bazán, J., Vinagre Aragón, A., and Martínez de Albéniz Zabaleta, M.

Published
2024
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8. 20919. ICTUS ISQUÉMICO POR EMBOLISMO TUMORAL COMO DEBUT DE UN ADENOCARCINOMA DE PULMÓN

Author

Albajar Gómez, I., Jauregui Larrañaga, C., Núñez Manjarres, G., Val-Carreres Castellote, A., de Burgos González, S., Escobar Padilla, A., Lijeron Farel, S., Ayuso García, D., Álvarez Agoues, K., Juaristi Abaunz, A., Marta Enguita, J., de la Riva Juez, P., Díez González, N., Pardina Vilella, L., de Arce Borda, A., González López, F., Equiza Bazán, J., Vinagre Aragón, A., and Martínez de Albéniz Zabaleta, M.

Published
2024
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10. Quality of life in idiopathic dystonia: a systematic review

Author

Girach, Ayesha, Vinagre Aragon, Ana, Zis, Panagiotis, Zis, Panagiotis [0000-0001-8567-3092], Vinagre Aragon, Ana [0000-0002-2368-3196], and Girach, Ayesha [0000-0001-8451-7127]

Subjects
medicine.medical_specialty, QoL, Neurology, Deep brain stimulation, medicine.medical_treatment, Blepharospasm, DBS, Disease, Review, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, BEB, Quality of life, medicine, otorhinolaryngologic diseases, Humans, 030212 general & internal medicine, Cervical dystonia, Dystonia, business.industry, medicine.disease, Botulinum toxin, humanities, CD, Dystonic Disorders, Quality of Life, BTX, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

OBJECTIVE: Dystonia is characterised by sustained muscular contractions frequently producing repetitive, twisting and patterned movements. The primary aim of this systematic review was to establish how quality of life (QoL) is affected in idiopathic focal, multifocal and segmental dystonia. This review aimed to evaluate variations in QoL between different subtypes of dystonia, identify the determinants of QoL and assess the effects of different treatments on QoL. METHODOLOGY: A systematic computer-based literature search was conducted using the PubMed database to search for papers on QoL in idiopathic focal, segmental, multifocal and generalized dystonia. We identified 75 studies meeting our inclusion criteria. Information was extracted regarding prevalence, demographics and response to treatment where indicated. RESULTS: This review revealed QoL to be a significant yet often overlooked issue in idiopathic dystonia. Data consistently showed that dystonia has a negative effect on QoL in patients compared to healthy controls, when measured using disease-specific and generic QoL measures. The majority of studies (n = 25) involved patients with cervical dystonia, followed by benign-essential blepharospasm (n = 10). Along with the beneficial effect to the dystonia symptoms, treatment using Botulinum Toxin and Deep Brain Stimulation is also effective in improving overall QoL across the majority of subtypes. CONCLUSION: The findings demonstrate that patients' QoL should routinely be assessed and monitored, as this may affect subsequent management. Further research will allow for more robust management of factors contributing to impaired QoL, aside from the physical defects found in dystonia. 266 12 2897 2906

Published
2018

11. 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
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12. The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

Author

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, Universidad de Sevilla, Bandres-Ciga, Sara, Ahmed, Sarah, Sabir, Marya S., Blauwendraat, Cornelis, Adarmes Gómez, A. D., Bernal-Bernal, Inmaculada, Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Carrillo, Fátima, Carrión-Claro, Mario, Gómez-Garre, Pilar, Jesús Maestre, Silvia, Labrador, Miguel Ángel, Macías García, Daniel, Méndez-Del Barrio, Carlota, Periñán, María Teresa, Tejera-Parrado, Cristina, Vargas-González, Laura, Díez-Fairen, Mónica, Álvarez, Ignacio, Tartari, J. P., Buongiorno, Maria Teresa, Aguilar, Miquel, Gorostidi, Ana, Bergareche, Jesús Alberto, Mondragon, Elisabet, Vinagre-Aragon, Ana, Croitoru, Ioana, Ruiz-Martínez, Javier, Dols-Icardo, Oriol, Kulisevsky, Jaime, Marín-Lahoz, Juan, Pagonabarraga-Mora, Javier, Pascual-Sedano, Berta, Ezquerra, Mario, Cámara, Ana, Compta, Yaroslau, Fernández Ortiga, Manel, Fernández-Santiago, Rubén, Muñoz, Esteban, Tolosa, Eduardo, Valldeoriola, Francesc, González-Aramburu, Isabel, Sanchez Rodriguez, Antonio, Sierra, María, Menéndez González, M., Blazquez, Marta, Garcia, Ciara, Suarez-San Martin, Esther, García-Ruíz, Pedro, Martínez-Castrillo, J. C., Vela-Desojo, Lydia, Ruz, Clara, Barrero, Francisco Javier, Escamilla-Sevilla, Francisco, Mínguez-Castellanos, Adolfo, Cerdan, Debora, Tabernero, César, Gomez Heredia, Maria Jose, Perez Errazquin, Francisco, Romero-Acebal, Manolo, Feliz, Cici, López-Sendón, José Luis, Mata, Marina, Martínez Torres, Irene, Kim, Jonggeol Jeffrey, Dalgard, Clifton L., Brooks, Janet, Saez-Atienzar, Sara, Gibbs, J. Raphael, Jorda, Rafael, Botia, Juan A., Bonet-Ponce, Luis, Morrison, Karen E., Clarke, Carl, Tan, Manuela, Morris, Huw, Edsall, Connor, Hernández, Dena, Simón-Sánchez, Javier, Nalls, Michael A., Scholz, Sonja, Jiménez Escrig, Adriano, Duarte, Jacinto, Vives, Francisco, Duran, Raquel, Hoenicka, Janet, Álvarez, Victoria, Infante, Jon, Martí, María-José, Clarimón, Jordi, López de Munain, Adolfo, Pastor, Pau, Mir, Pablo, Singleton, Andrew B., 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, Universidad de Sevilla, Bandres-Ciga, Sara, Ahmed, Sarah, Sabir, Marya S., Blauwendraat, Cornelis, Adarmes Gómez, A. D., Bernal-Bernal, Inmaculada, Bonilla-Toribio, Marta, Buiza-Rueda, Dolores, Carrillo, Fátima, Carrión-Claro, Mario, Gómez-Garre, Pilar, Jesús Maestre, Silvia, Labrador, Miguel Ángel, Macías García, Daniel, Méndez-Del Barrio, Carlota, Periñán, María Teresa, Tejera-Parrado, Cristina, Vargas-González, Laura, Díez-Fairen, Mónica, Álvarez, Ignacio, Tartari, J. P., Buongiorno, Maria Teresa, Aguilar, Miquel, Gorostidi, Ana, Bergareche, Jesús Alberto, Mondragon, Elisabet, Vinagre-Aragon, Ana, Croitoru, Ioana, Ruiz-Martínez, Javier, Dols-Icardo, Oriol, Kulisevsky, Jaime, Marín-Lahoz, Juan, Pagonabarraga-Mora, Javier, Pascual-Sedano, Berta, Ezquerra, Mario, Cámara, Ana, Compta, Yaroslau, Fernández Ortiga, Manel, Fernández-Santiago, Rubén, Muñoz, Esteban, Tolosa, Eduardo, Valldeoriola, Francesc, González-Aramburu, Isabel, Sanchez Rodriguez, Antonio, Sierra, María, Menéndez González, M., Blazquez, Marta, Garcia, Ciara, Suarez-San Martin, Esther, García-Ruíz, Pedro, Martínez-Castrillo, J. C., Vela-Desojo, Lydia, Ruz, Clara, Barrero, Francisco Javier, Escamilla-Sevilla, Francisco, Mínguez-Castellanos, Adolfo, Cerdan, Debora, Tabernero, César, Gomez Heredia, Maria Jose, Perez Errazquin, Francisco, Romero-Acebal, Manolo, Feliz, Cici, López-Sendón, José Luis, Mata, Marina, Martínez Torres, Irene, Kim, Jonggeol Jeffrey, Dalgard, Clifton L., Brooks, Janet, Saez-Atienzar, Sara, Gibbs, J. Raphael, Jorda, Rafael, Botia, Juan A., Bonet-Ponce, Luis, Morrison, Karen E., Clarke, Carl, Tan, Manuela, Morris, Huw, Edsall, Connor, Hernández, Dena, Simón-Sánchez, Javier, Nalls, Michael A., Scholz, Sonja, Jiménez Escrig, Adriano, Duarte, Jacinto, Vives, Francisco, Duran, Raquel, Hoenicka, Janet, Álvarez, Victoria, Infante, Jon, Martí, María-José, Clarimón, Jordi, López de Munain, Adolfo, Pastor, Pau, Mir, Pablo, and Singleton, Andrew B.

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.

Published
2019

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