Citations 2
Chromosome X-wide association study in multiple system atrophy identifies sex-differential risk loci
Ray, Anindita , Chia, Ruth , Rasheed, Memoona, Ece, Bayram, Jinhui, Ding, Walton, Ronald L., Diez-Fairen, Monica, Álvarez, Ignacio Morales, Fanciulli, Alessandra , Seppi, Mag Klaus, Duerr, Susanne, Leys, Fabian , Krismer, Florian , Sidoroff, Victoria , Pirker, Walter , Rascol, Olivier, Foubert-Samier, Alexandra, Meissner, Wassilios G, Tison, François , Barone, Paolo, Russillo, Maria Claudia, Marín-Lahoz, Juan, Kulisevsky, J, Torres, Soraya, Mir, Pablo, Periñán, María Teresa, Proukakis, C., Goh, Yee Yen, Parkkinen, Laura, Hu, Michele T, Saxon, Jennifer A. , Rollinson, Sara , Garland, Emily M. , Litvan, Irene, Alcalay, Roy N, Kwei, Kimberly , Lubbe, Steven, Mao, Qinwen, Flanagan, Margaret E, Castellani, Rudolph J, Ndayisaba, Alain , Calvo, Andrea, Canosa, Antonio, Bohannan, Ryan C., Norcliffe-Kaufmann, Lucy, Palma, Jose-Alberto, Dawson, Ted M, Albert, Marilyn S, Pletniková, Olga , Troncoso, Juan C, Lage, Carmen , Sánchez-Juan, Pascual, Serrano, Geidy E, Beach, Thomas G, Morris, Huw R, Clarimon, Jordi, Jaunmuktane, Zane, Révész, Tamás, Warner, Tom, Hardy, John A, Ryten, Mina, Ferrucci, Luigi, Topol, Eric, Torkamani, Ali, DeCasien, Alex R, Chiò, Adriano, Low, Philip, Wszolek, Zbigniew K, Dickson, Dennis W., Traynor, Bryan J, Gibbs, J Raphael, Dalgard, Clifton L, Ross, Owen A, Houlden, Henry, Scholz, Sonja W., Hardy, John , Dickson, Dennis W. , Ross, Owen A. , Houlden, Henry , Scholz, Sonja W. , Chia, Ruth , Proukakis, Christos , Dickson, Dennis W , Dalgard, Clifton L , Ross, Owen A , Houlden, Henry , Scholz, Sonja W , Hardy, John , Reynolds, Regina H. , Díez-Fairén, Mónica , Fanciulli, Alessandra , Stefanova, Nadia , Seppi, Klaus , Krismer, Florian, Zimprich, Alexander , Rascol, Olivier , Foubert‐Samier, Alexandra , Meissner, Wassilios G. , Tison, François , Traon, Anne Pavy‐Le , Pellecchia, Maria Teresa , Marín‐Lahoz, Juan , Kulisevsky, Jaime , Mir, Pablo , Chelban, Viorica , Wu, Lesley , Kobylecki, Christopher , Biaggioni, Italo , Litvan, Irene , Rubio, Ileana, Lubbe, Steven , Flanagan, Margaret E , Castellani, Rudolph J. , Khurana, Vikram , Mora, Gabriele , Floris, Gianluca , Moore, Anni K. , Norcliffe‐Kaufmann, Lucy , Palma, Jose-Alberto , Kaufmann, Horacio , Dawson, Ted M , Rosenthal, Liana S. , Pantelyat, Alexander , Troncoso, Juan C. , Infante, Jon , Serrano, Geidy E. , Beach, Thomas G. , Pástor, Pau , Albani, Diego , Clarimón, Jordi , Jaunmuktane, Zane , Frontzek, Karl , Warner, Thomas T. , Ferrucci, Luigi , Topol, Eric J. , Torkamani, Ali , DeCasien, Alex R. , Chiò, Adriano , Singer, Wolfgang , Cheshire, William P. , Wszołek, Zbigniew K. , Traynor, Bryan J. , Gibbs, J. Raphael
Brain | February 12, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.
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.