Citations 3
Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa‐Induced Dyskinesia
Sosero, Yuri L. , Bandrés‐Ciga, Sara , Tocino, Maria Teresa Periñan, Belloso, Dìaz R., Gómez‐Garre, Pilar , Faouzi, Johann , Pavelka, Lukas , Marques, Tainá M. , May, Patrick , Milanowski, Łukasz , Uitti, Ryan J. , Hilten, Jacobus J. van , Simon, David K. , Eberly, Shirley , Krohn, Lynne , Freeman, Kathryn , Ruskey, Jennifer A. , Asayesh, Farnaz , Menéndez‐González, Manuel , Pástor, Pau , Ross, Owen A. , Krüger, Rejko , Kõks, Sulev, Mir, Pablo , Klucken, Jochen , Gómez‐Garre, Pilar , Fatima, Noor , Gómez-Garre, Pilar , May, Patrick , Milanowski, Łukasz M , Wszolek, Z.K. , Simon, David K , Ross, Owen A , Corvol, Jean-Christophe , Koks, Sulev , Mir, Pablo , de Bie, Rob M A , Iwaki, Hirotaka , Gan-Or, Ziv , Pastor, Pau , Ferwerda, Bart , Taba, Pille , Gomes, Clarissa P. C. , Kolodkin, Alexey N. , Wszołek, Zbigniew K. , Heutink, Peter , Álvarez, Ignacio , Yu, Eric , Freeman, Kathryn, Rudakou, Uladzislau , Corvol, Jean‐Christophe , Bie, Rob M.A. de , Gan‐Or, Ziv
Movement Disorders | August 12, 2024 | Volume: 39 | Issue: 10 | Pages: 1773-1783
Abstract Background Levodopa‐induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2 . Objectives Our goal was to investigate the effects of genetic variants on risk and time to LID. Methods We performed a genome‐wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. Results We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21–2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09–1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth_quartile = 1.27; 95% CI, 1.03–1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third_quartile = 1.38; 95% CI, 1.07–1.79; P = 0.0128; HR fourth_quartile = 1.38; 95% CI = 1.06–1.78; P = 0.0147). Conclusions This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Guen, Yann Le , Luo, Guo , Damotte, Vincent , Jansen, Iris E. , Nicolas, Aude , Rojas, Itziar de, Bellenguez, Céline , Lian, Michelle Mulan , Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier‐Boley, Benjamin , Naito, Tatsuhiko , Talyansky, Seth D., Yogeshwar, Selina , Sempere, Vicente Peris, Satake, Wataru , Álvarez, Victoria , Arosio, Beatrice , Boland, Anne , Daniele, Antonio , Darling, D.H., Dichgans, Martin , Dufouil, Carole , Düzel, Emrah , García‐Ribas, Guillermo, García‐Alberca, José María , García-González, Pablo, Giedraitis, Vilmantas , Graff, Caroline , Grünblatt, Edna , Hausner, Lucrezia , Jung, Yoo Jin , Deckert, Jürgen, Kern, Silke , Kuulasmaa, Teemu , Lee, Kun Ho , Lin, Ling , Masullo, Carlo , Mehrabian, Shima , Mendonça, Alexandre de , Boada, Merçé , Mir, Pablo , Moreno, Fermín , Nicolas, Gaël , Niida, Shumpei , Nordestgaard, Børge G. , Papenberg, Goran, Papma, Janne M., Pástor, Pau , Peters, Oliver , Popp, Julius , Molina‐Porcel, Laura , Puerta, Raquel , Pérez‐Tur, Jordi , Ramakers, Inez H.G.B. , Real, Luís Miguel , Riedel‐Heller, Steffi G. , Rodríguez‐Rodríguez, Eloy , Ross, Owen A. , Scarmeas, Nikolaos , Schneider, Anja , Solfrizzi, Vincenzo , Spalletta, Gianfranco , Tan, Eng‐King , Tegos, Thomas, Thomassen, Jesper Qvist , Tremolizzo, Lucio , Verhey, Frans, EADB, group, GR@ACE study, DemGene, EADI, GERAD, Blennow, Kaj , He, Zihuai , Jessen, Frank , Kehoe, Patrick G. , Duin, Cornelia van, Sánchez‐Juan, Pascual , Zettergren, Anna , Okada, Yukinori , Rossi, Giacomina, Gim, Jungsoo , Sims, Rebecca, Ramı́rez, Alfredo , Lambert, Jean‐Charles , Greicius, Michael D. , Mignot, Emmanuel , Moreno–Grau, Sonia , Rojas, Itziar de, Prokic, Ivana, Aarsland, Dag, García‐González, Pablo , Abdelnour, Carla , Armstrong, Nicola J. , Anthoula, Tsolaki, Archetti, Silvana, Pastor, Alfonso Arias, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa , Baquero, Miquel , Pastor, Ana Belén , Besse, Céline , Bizarro, Alessandra, Blesa, Rafael , Bossù, Paola , Brusco, 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Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort
Vollstedt, Eva‐Juliane , Schaake, Susen , Lohmann, Katja , Lesage, Suzanne , Tesson, Christelle , Wurster, Isabel , Hentati, F., Marder, Karen, Waters, Cheryl , Fahn, Stanley, Brüggemann, Norbert , Tolosa, Eduardo , Garrido, Alícia , Annesi, Grazia , Bozi, Maria , Ferreira, Joaquim J. , Guedes, Leonor Correia , Petrucci, Simona , Clark, Lorraine N. , Abramycheva, Natalya, Menéndez‐González, Manuel , Maestre, S. Jesús, Gómez‐Garre, Pilar , Mir, Pablo , Ran, Caroline , Kuo, Ming‐Che , Ross, Owen A. , Williams‐Gray, Caroline H. , Camacho, Marta , Cornejo‐Olivas, Mario , Torres-Ramírez, Luis , Wu, Yih‐Ru , Morgadinho, Ana , Berg, Daniela , Kuhlenbäumer, Gregor , Kühn, Andrea A. , Borngräber, Friederike , Michele, Giuseppe De , Rosa, Anna De , Zimprich, Alexander , Puschmann, Andreas , Mellick, George D. , Chase, Bruce A. , Markopoulou, Katerina , Satake, Wataru , Rossi, Malco , Lynch, Timothy , Olszewska, Diana A. , Lim, Shen‐Yang , Ahmad‐Annuar, Azlina , Tan, Ai Huey , Hanağası, Haşmet , Koziorowski, Dariusz , Ertan, Sibel , Genç, Gençer , Saunders‐Pullman, Rachel , Warrenburg, Bart van de, Bressman, Susan , Toft, Mathias , Appel‐Cresswell, Silke , Boon, Agnita J.W. , Krüger, Rejko , Sammler, Esther , Tumas, Vítor , Zhang, Baorong , Garraux, Gaëtan , Kim, Yun Joong , Winkelmann, Juliane , Sue, Carolyn M. , Tan, Eng‐King , Kostić, Vladimir , Arkadir, David , Martikainen, Mika H. , Brighina, Laura , Suchowersky, Oksana , Rieß, Olaf , Das, Parimal, Mollenhauer, Brit , Gatto, Emilia , Petersen, Maria Skaalum , Aasly, Jan , Aasly, Anna, Farrer, Matthew J. , Brockmann, Kathrin , Klein, Christine , Group, the MJFF Global Genetic Parkinson's Disease Study, Bardien, Soraya , Barrett, Matthew J. , Januário, Cristina , Sousa, Mário , Soto‐Beasley, Alexandra I. , May, Patrick , Mirelman, Anat , Brüggemann, Norbert , Borsche, Max , Tolosa, Eduardo , Ferreira, Joaquim J , Alvarez, Victoria , Mir, Pablo , Kuo, Ming-Che , Ross, Owen A , Nishioka, Kenya , Williams-Gray, Caroline H , Camacho, Marta , Cornejo-Olivas, Mario , Wu, Yih-Ru , Termsarasab, Pichet , Borngräber, Friederike , Zimprich, Alexander , Gambardella, Stefano , Chase, Bruce , Olszewska, Diana A , Tan, Ai Huey , Barkhuizen, Melinda , Appel-Cresswell, Silke , Skorvanek, Matej , Sammler, Esther M , Zhang, Baorong , Chung, Sun Ju , Puschmann, Andreas , Januário, Cristina , Klein, Christine , Bardien, Soraya , Toft, Mathias , Koziorowski, Dariusz , May, Patrick , Beasley, Alexandra I , Barrett, Matthew J , Sue, Carolyn M , Kühn, Andrea A , Padmanabhan, Shalini , Brice, Alexis , Vidailhet, Marie , Giladi, Nir , Kasten, Meike , Borsche, Max , Foroud, Tatiana , Gagliardi, Monica , Stefanis, Leonidas , Avenali, Micol , Fedotova, E. Yu. , Álvarez, Victoria , Belin, Andrea Carmine , Lin, Chin‐Hsien , Crosiers, David , Wszołek, Zbigniew K. , Jankovic, Joseph J. , Funayama, Manabu , Clarimón, Jordi , Lee‐Chen, Guey‐Jen , Pulkes, Teeratorn , Dorszewska, Jolanta , Carr, Jonathan , Ferese, Rosangela , Toda, Tatsushi , Merello, Marcelo , Al-Mubarak, Bashayer R , Aguiar, Patrícia de Carvalho , Pimentel, Márcia Mattos Gonçalves , Warrenburg, Bart P.C. van de , Lang, Anthony E. , Damásio, Joana , Klivènyi, Péter , Borges, Vanderci , Hertz, Jens Michael , Spitz, Mariana , Hattori, Nobutaka , Wu, Ruey‐Meei , Illarioshkin, Sergey Nikolaevich , Valente, Enza Maria , Alcalay, Roy N. , Thaler, Avner , Corvol, Jean‐Christophe , Group, the MJFF Global Genetic Parkinson's Disease Study
Movement Disorders | January 24, 2023 | Volume: 38 | Issue: 2 | Pages: 286-303
AbstractBackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.ResultsWe collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.ConclusionsWithin the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.