Molina-Porcel, Laura
Mayo Clinic
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Fundació Recerca Clínic Barcelona (FRCB), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Citations 3
Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells
Wang, Hui , Chang, Timothy S. , Dombroski, Beth A. , Cheng, Po‐Liang , Si, Yaqin , Tucci, Albert , Patil, Vishakha, Valiente‐Banuet, Leopoldo , Li, Chong , Farrell, Kurt , Molina‐Porcel, Laura , Rajput, Alex , Gearing, Marla , Newell, Kathy L. , Rábano‐Gutierrez, Alberto, Oertel, Wolfgang H. , Respondek, Gesine , Stamelou, María , Arzberger, Thomas , Roeber, Sigrun, Müller, Ulrich , Pástor, Pau , Ber, Isabelle Le, Beach, Thomas G. , Litvan, Irene , Rademakers, Rosa , Ross, Owen A. , Boxer, Adam L. , Seeley, Willian W., Lee, Edward B. , Silva, Rohan de , Crary, John F. , Goate, Alison , Friedman, Jeffrey S., Compta, Yaroslau , Coppola, Giovanni , Wang, Li‐San , Group, PSP Genetics Study, Tzeng, Jung‐Ying , Geschwind, Daniel H. , Schellenberg, Gerard D. , Si, Ya-Qin , Mclean, Catriona , Molina-Porcel, Laura , Rajput, Alex , Deyn, Peter Paul De , Le Bastard, Nathalie , Gearing, Marla , Donker Kaat, Laura , Van Swieten, John C , Ghetti, Bernardino F , Troakes, Claire , de Yébenes, Justo G , Meller, Tina , Oertel, Wolfgang H , Respondek, Gesine , Hopfner, Franziska , Pastor, Pau , Brice, Alexis , Dürr, Alexandra , Beach, Thomas G , Serrano, Geidy E , Hazrati, Lili‐Naz , Litvan, Irene , Ross, Owen A , Galasko, Douglas , Boxer, Adam , Miller, Bruce L , Deerlin, Vivianna M. Van , Lee, Edward B , White, Charles L , Morris, Huw R , Crary, John F , Goate, Alison M , Leung, Yuk Yee , Wang, Li-San , Dickson, Dennis W , Höglinger, Günter U , Tzeng, Jung-Ying , Schellenberg, Gerard D , Lee, Wan-Ping , Dombroski, Beth , Farrell, Kurt , McLean, Catriona , Kaat, Laura Donker , Swieten, John C. van , Dopper, Elise G.P. , Ghetti, Bernardino , Troakes, Claire , Müller, Ulrich, Hopfner, Franziska , Brice, Alexis , Ber, Isabelle Le , Serrano, Geidy E. , Galasko, Douglas , Miller, Bruce L. , White, Charles L. , Morris, Huw R. , Naj, Adam Christian , Group, PSP Genetics Study, Dalgard, Clifton L. , Dickson, Dennis W. , Höglinger, Günter U.
Movement Disorders | March 12, 2025 | Volume: 40 | Issue: 5 | Pages: 950-961
AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 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, Luis Ignacio , Buiza‐Rueda, Dolores, Bürger, Katharina , Burholt, Vanessa, Cecchetti, Roberta, Chillotti, Caterina , Ciccone, Simona, Claassen, Jurgen A.H.R., Clark, Christopher , Costantini, Emanuele Maria , Daian, Delphine , Dartigues, Jean‐François, Escott-Price, Valentina, Ewers, Michael , Fernández‐Fuertes, Marta , Ferreira, Catarina B. , Fin, Bertrand, Fließbach, Klaus , Franco-Macías, Emlio, García-González, Pablo, García‐Madrona, Sebastián, Giegling, Ina, Giorgio, Giaccone, González-Pérez, Antonio, Grande, Giulia , Green, Emma , Grimmer, Timo, Hardy, John, Hartmann, Annette M. , Harwood, Janet , Helisalmi, Seppo , Hernández, Isabel, Hoffmann, Per, Vilas, Raquel Huerto, Hulsman, Marc , Johansson, Charlotte , Kilander, Lena, Ståhlbom, Anne Kinhult, Koivisto, Anne M. , Lage, Carmen , Lerch, Ondřej , Munain, Adolfo Lopez de, Löwemark, Malin, Luckcuck, Lauren, Maier, Wolfgang, Marco, Spallazzi, Montes, Ángel Martín, Rodríguez, Carmen Martínez, Meggy, Alun, Mendoza, Silvia, Moebus, 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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.
Common Variants Near ZIC1 and ZIC4 in Autopsy‐Confirmed Multiple System Atrophy
Hopfner, Franziska , Tietz, Anja, Ruf, Viktoria , Ross, Owen A. , Koga, Shunsuke , Attems, Johannes , Beach, Thomas, Beller, Allison , Duyckaerts, Charles, Evsyukov, Valentin, Flanagan, Margaret E. , Frosch, Matthew P. , Gearing, Marla , Gelpí, Ellen , Gerpen, Jay A. van, Glass, Jonathan D. , Grinberg, Lea T. , Halliday, Glenda M. , Höllerhage, Matthias , Huitinga, Inge , Keene, Dirk, Kovács, Gábor G. , Lee, Edward B. , Xiong, Chengjie , Martı́, Marı́a José , Mackenzie, Ian R. , Mollenhauer, Brit , Neumann, Manuela , Newell, Kathy L. , Pendziwiat, Manuela , Molina‐Porcel, Laura , Rábano, Alberto , Rajput, Alex, Rajput, Ali H. , Reimann, Regina , Selvackadunco, Sashika , Simuni, Tanya , Svenningsson, Per , Trenkwalder, Claudia , Troakes, Claire , Trojanowski, John Q. , Uitti, Ryan J. , Xie, Tao , Ximelis, Teresa , Yebenes, Justo, Müller, Ulrich , Schellenberg, Gerard D., Herms, Jochen , Kuhlenbäumer, Gregor , Deuschl, Günther , Gelpi, Ellen , Van Gerpen, Jay A, Halliday, Glenda , Irwin, David J , Mollenhauer, Brit , Pantelyat, Alex , Svenningsson, Per , Höglinger, Günter U , Koga, Shunsuke , Ross, Owen A , Kovacs, Gabor G , Xiong, Chengjie , Grinberg, Lea , Molina-Porcel, Laura , Troakes, Claire , Hopfner, Franziska , Lee, Edward B , Simuni, Tanya , Dickson, Dennis W. , Aguzzi, Adriano , Cheshire, William P. , Deerlin, Vivianna M. Van , Desplats, Paula , Deuschl, Günther , Duyckaerts, Charles , Ellinghaus, David , Franke, André , Ghetti, Bernardino , Helbig, Ingo , Irwin, David J. , McKeith, Ian G. , McLean, Catriona , Pantelyat, Alexander , Peters, Annette , Matěj, Radoslav , Scott, William K. , Seeley, William W. , Stadelmann, Christine , Thomas, Alan , White, Charles L. , Wszołek, Zbigniew K. , Schellenberg, Gerard D., Höglinger, Günter U.
Movement Disorders | August 23, 2022 | Volume: 37 | Issue: 10 | Pages: 2110-2121
ABSTRACT Background Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society