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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

2021; Nature Portfolio; Volume: 53; Issue: 3 Linguagem: Inglês

10.1038/s41588-021-00785-3

1546-1718

Ruth Chia, Marya S. Sabir, Sara Bandrés‐Ciga, Sara Sáez-Atiénzar, Regina H. Reynolds, Emil K. Gustavsson, Ronald L. Walton, Sarah Ahmed, Coralie Viollet, Jinhui Ding, Mary B. Makarious, Mónica Díez-Fairén, Makayla K. Portley, Zalak Shah, Yevgeniya Abramzon, Dena Hernández, Cornelis Blauwendraat, David J. Stone, John D. Eicher, Laura Parkkinen, Olaf Ansorge, Lorraine N. Clark, Lawrence S. Honig, Karen Marder, Afina W. Lemstra, Peter St George‐Hyslop, Elisabet Londos, Kevin Morgan, Tammaryn Lashley, Thomas T. Warner, Zane Jaunmuktane, Douglas Galasko, Isabel Santana, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, Vivianna M. Van Deerlin, John Q. Trojanowski, Maurizio Grassano, Andrea Calvo, Gabriele Mora, Antonio Canosa, Gianluca Floris, Ryan C. Bohannan, Francesca Brett, Ziv Gan‐Or, Joshua T. Geiger, Anni Moore, Patrick May, Rejko Krüger, David S. Goldstein, Grisel Lopez, Nahid Tayebi, Ellen Sidransky, Anthony R. Sotis, Gauthaman Sukumar, Camille Alba, Nathaniel M. Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bačíková, Xijun Zhang, Daniel Hupalo, Adelani Adeleye, Matthew D. Wilkerson, Harvey B. Pollard, Lucy Norcliffe‐Kaufmann, Jose‐Alberto Palma, Horacio Kaufmann, Vikram G. Shakkottai, Matthew Perkins, Kathy L. Newell, Thomas Gasser, Claudia Schulte, Francesco Landi, Erika Salvi, Daniele Cusi, Eliezer Masliah, Ronald C. Kim, Chad A. Caraway, Edwin S. Monuki, Maura Brunetti, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Margaret E. Flanagan, Qinwen Mao, Eileen H. Bigio, Eloy Rodríguez‐Rodríguez, Jon Infante, Carmen Lage, Isabel González Aramburu, Pascual Sánchez-Juan, Bernardino Ghetti, Julia Keith, Sandra E. Black, Mario Masellis, Ekaterina Rogaeva, Charles Duyckaerts, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Matthew J. Barrett, Bension S. Tilley, Steve Gentleman, Giancarlo Logroscino, Geidy E. Serrano, Thomas G. Beach, Ian G. McKeith, Alan Thomas, Johannes Attems, Christopher M. Morris, Lyle J. Palmer, Seth Love, Claire Troakes, Safa Al‐Sarraj, Angela Hodges, Dag Aarsland, Gregory Klein, Scott M. Kaiser, Randy Woltjer, Pau Pástor, Lynn M. Bekris, James B. Leverenz, Lilah M. Besser, Amanda Kuzma, Alan E. Renton, Alison Goate, David A. Bennett, Clemens R. Scherzer, Huw R. Morris, Raffaele Ferrari, Diego Albani, Stuart Pickering‐Brown, Kelley Faber, Walter A. Kukull, Estrella Morenas‐Rodríguez, Alberto Lleó, Juan Fortea, Daniel Alcolea, Jordi Clarimón, Mike A. Nalls, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, Tatiana Foroud, Caroline Graff, Zbigniew K. Wszołek, Tanis J. Ferman, Bradley F. Boeve, John Hardy, Eric J. Topol, Ali Torkamani, Andrew Singleton, Mina Ryten, Dennis W. Dickson, Adriano Chiò, Owen A. Ross, J. Raphael Gibbs, Clifton L. Dalgard, Bryan J. Traynor, Sonja W. Scholz,

Bioinformatics and Genomic Networks

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition. Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.