Citations 5
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
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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.
Alpha‐synuclein repeat variants and survival in Parkinson's disease
Armasu, Sebastian M. , Anderson, Kari, Frigerio, Roberta , Aasly, Jan , Annesi, Grazia , Bentivoglio, Anna Rita , Brighina, Laura , Chartier‐Harlin, Marie‐Christine , Goldwurm, Stefano , Jasińska‐Myga, Barbara, Jeon, Beom Seok , Kim, Yun Joong , Krüger, Rejko , Lesage, Suzanne , Markopoulou, Katerina , Mellick, George D. , Morrison, Karen , Puschmann, Andreas , Tan, Eng‐King , Crosiers, David , Broeckhoven, Christine Van , Wirdefeldt, Karin , Maraganore, Demetrius M. , Chung, Sun Ju , Biernacka, Joanna M. , Hadjigeorgiou, Georgios M. , Theuns, Jessie , Wszołek, Zbigniew K. , Elbaz, Alexis , Puschmann, Andreas
Movement Disorders | February 27, 2014 | Volume: 29 | Issue: 8 | Pages: 1053-1057
ABSTRACT Objectives To determine whether α‐synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). Methods Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow‐up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. Results Twenty‐one sites contributed data for 6,154 cases. There was no significant association between α‐synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01‐1.10; P value = 0.01). Conclusions In our large consortium study, α‐synuclein REP1 genotypes were not associated with survival in PD. Further studies of α‐synuclein's role in disease progression and long‐term outcomes are needed. © 2014 International Parkinson and Movement Disorder Society
Population‐specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO‐PD) consortium
Soto‐Ortolaza, Alexandra I., Aasly, Jan , Abahuni, Nadine, Annesi, Grazia , Bacon, Justin A., Bardien, Soraya , Bozi, Maria , Brice, Alexis , Brighina, Laura , Carr, Jonathan , Chartier‐Harlin, Marie‐Christine , Dardiotis, Efthimios , Dickson, Dennis W. , Diehl, Nancy N. , Ferrarese, Carlo , Fiske, Brian , Gibson, Rachel A. , Hattori, Nobutaka , Ioannidis, John P. A. , Boczarska‐Jedynak, Magdalena , Jasińska‐Myga, Barbara, Jeon, Beom S., Kim, Yun Joong , Klein, Christine , Krüger, Rejko , Kyratzi, Elli, Lesage, Suzanne , Lin, Chin‐Hsien , Lynch, Timothy , Maraganore, Demetrius M. , Mellick, George D. , Mutez, Eugénie , Opala, Grzegorz, Park, Sung Sup , Petrucci, Simona , Puschmann, Andreas , Quattrone, Aldo , Sharma, Manu , Silburn, Peter A., Sohn, Young H. , Tadić, Vera, Theuns, Jessie , Tomiyama, Hiroyuki , Uitti, Ryan J. , Valente, Enza Maria , Broeckhoven, Christine Van , Loo, Simone van de, Vassilatis, Demetrios K. , Vilariño‐Güell, Carles , White, Linda R., Wirdefeldt, Karin , Wu, Ruey‐Meei , Hentati, Fayçal, Farrer, Matthew J. , Ross, Owen A. , Soto‐Beasley, Alexandra I. , Heckman, Michael G. , Elbaz, Alexis , Gibson, Jonathan M. , Hadjigeorgiou, Georgios M. , Nilsson, Christer C. , Stefanis, Leonidas , Wszołek, Zbigniew K. , Dickson, Dennis W , Ross, Owen A , Puschmann, Andreas , Klein, Christine , Bardien, Soraya , Mutez, Eugénie , Valente, Enza Maria , Ioannidis, John P A , Beasley, Alexandra I , Carr, Jonathan , Brice, Alexis , Lin, Chin-Hsien , Wu, Ruey-Meei
Movement Disorders | August 2, 2013 | Volume: 28 | Issue: 12 | Pages: 1740-1744
ABSTRACTBackgroundVariants within the leucine‐rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine‐rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late‐onset sporadic disorders like Parkinson's disease.MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine‐rich repeat kinase 2 gene across 23 different sites in 15 countries.ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K‐R1398H‐K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.ConclusionsEstablishing individual patient‐based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society
A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants
Sharma, Manu , Aasly, Jan , Annesi, Grazia , Brice, Alexis , Bozi, Maria , Barcikowska, Maria , Crosiers, David , Clarke, Carl E , Facheris, Maurizio , Farrer, Matthew J. , Garraux, Gaëtan , Gispert, Suzana, Auburger, Georg , Vilariño‐Güell, Carles , Hicks, Andrew A. , Hattori, Nobutaka , Jeon, Beom S., Jamrozik, Zygmunt , Krygowska‐Wajs, Anna, Lesage, Suzanne , Lill, Christina M. , Lin, Juei‐Jueng , Lynch, Timothy , Lichtner, Peter , Lang, Anthony E. , Libioulle, Cécile , Murata, Miho, Mok, Vincent , Jasińska‐Myga, Barbara, Mellick, George D. , Morrison, Karen , Meitnger, Thomas, Zimprich, Alexander , Opala, Grzegorz, Pramstaller, Peter P. , Pichler, Irene , Park, Sung Sup , Quattrone, Aldo , Ross, Owen A. , Stockton, Joanne , Satake, Wataru , Silburn, Peter A., Strom, Tim M., Theuns, Jessie , Tan, Eng King, Tomiyama, Hiroyuki , Uitti, Ryan J. , Broeckhoven, Christine Van , Wirdefeldt, Karin , Xiromerisiou, Georgia , Yomono, Harumi, Yueh, Kuo-Chu, Zhao, Yi , Gasser, Thomas , Maraganore, Demetrius M. , Krüger, Rejko , Ioannidis, John P. A. , Bertram, Lars , Hadjigeorgiou, Georgios M. , Rogaeva, Ekaterina A. , Stefanis, Leonidas , Toda, Tatsushi , Wszołek, Zbigniew K. , Lang, Anthony E , Ross, Owen A , Zimprich, Alexander , Brice, Alexis
Journal of Medical Genetics | November 2, 2012 | Volume: 49 | Issue: 11 | Pages: 721-726
Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
Large-scale replication and heterogeneity in Parkinson disease genetic loci
Sharma, Manu , Aasly, Jan , Annesi, Grazia , Brice, Alexis , Broeckhoven, Christine Van , Bozi, Maria , Crosiers, David , Clarke, Carl E , Facheris, Maurizio , Farrer, Matthew J. , Garraux, Gaëtan , Gispert, Suzana, Auburger, Georg , Vilariño‐Güell, Carles , Hicks, Andrew A. , Hattori, Nobutaka , Jeon, Beom S., Lesage, Suzanne , Lill, Christina M. , Lin, Juei-Jueng, Lynch, Timothy , Lichtner, Peter , Lang, Anthony E. , Jasińska‐Myga, Barbara, Mellick, George D. , Morrison, Karen , Opala, Grzegorz, Pramstaller, Peter P. , Pichler, Irene , Park, Sung Sup , Quattrone, Aldo , Ross, Owen A. , Stockton, Joanne , Satake, Wataru , Silburn, Peter A., Theuns, Jessie , Tan, Eng-King, Tomiyama, Hiroyuki , Uitti, Ryan J. , Wirdefeldt, Karin , Xiromerisiou, Georgia , Yueh, Kuo-Chu, Zhao, Yi , Gasser, Thomas , Maraganore, Demetrius M. , Krüger, Rejko , Boyle, R.S, Sellbach, A, Siebert, G., Pickut, Barbara , Engelborghs, Sebastiaan , Meeus, Bram, Deyn, Peter Paul De, Cras, Patrick , Agid, Yves, Anheim, Mathieu , Bonnet, A-M, Broussolle, E. , Corvol, Jean‐Christophe , Destée, A., Durif, F., Lesage, Suzanne , Lohmann, Ebba , Pollak, Pierre, Rascol, Olivier , Tison, François , Viallet, François, Amouyel, Philippe , Loriot, Marie‐Anne , Mutez, Eugénie , Duflot, Aurélie , Legendre, Jean-Philippe, Waucquier, Nawal, Schulte, Claudia , Klein, Christine , Djarmati, Ana, Hagenah, Johann, Lohmann, Katja , Hilker, Rüdiger, Loo, Simone van de, Tsimourtou, Vaïa, Ralli, Styliani, Kountra, Persa, Patramani, Gianna, Vogiatzi, Cristina, Hattori, Nobutaka, Yoshino, Hiroyo , Li, Yuanzhe, Imamichi, Yoko, Gibson, J. Mark , Ialongo, Tàmara, Brighina, Laura , Corradi, B., Piolti, Roberto, Tarantino, Patrizia, Kłodowska-Duda, Gabriela, Boczarska‐Jedynak, Magdalena , Tan, Eng King, Olson, Lars, Westerlund, Marie, Sydow, Olof , Puschmann, Andreas , Lin, J-J , J, Eric Ahlskog, Lesnick, Timothy G. , Rocca, Walter A. , Checkoway, Harvey , Westenberger, Ana , Ioannidis, John P. A. , Bertram, Lars , Hadjigeorgiou, Georgios M. , Mok, Vincent , Rogaeva, Ekaterina A. , Stefanis, Leonidas , Toda, Tatsushi , Wszołek, Zbigniew K. , O’Sullivan, John D. , Sutherland, Greg T. , Dissanayaka, Nadeeka N. , Borg, Michael , Damier, Philippe , Dürr, Alexandra , Tranchant, Christine , Vidailhet, Marie , Tzourio, Christophe , Rieß, Olaf , Berg, Daniela , Dardiotis, Efthimios , Funayama, Manabu , Valente, Enza Maria , Ferraris, Alessandro , Dallapiccola, Bruno , Annesi, Ferdinanda , Belin, Andrea Carmine , Olson, Lars, Galter, Dagmar , Nilsson, Christer C. , Andrade, Mariza de , Lang, Anthony E , Ross, Owen A , Puschmann, Andreas , Klein, Christine , Amouyel, Philippe , Corvol, Jean-Christophe , Mutez, Eugénie , Schulte, Claudia , Brice, Alexis
Neurology | July 12, 2012 | Volume: 79 | Issue: 7 | Pages: 659-667