1. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias
- Author
-
Karri Kaivola, Ruth Chia, Jinhui Ding, Memoona Rasheed, Masashi Fujita, Vilas Menon, Ronald L. Walton, Ryan L. Collins, Kimberley Billingsley, Harrison Brand, Michael Talkowski, Xuefang Zhao, Ramita Dewan, Ali Stark, Anindita Ray, Sultana Solaiman, Pilar Alvarez Jerez, Laksh Malik, Ted M. Dawson, Liana S. Rosenthal, Marilyn S. Albert, Olga Pletnikova, Juan C. Troncoso, Mario Masellis, Julia Keith, Sandra E. Black, Luigi Ferrucci, Susan M. Resnick, Toshiko Tanaka, Eric Topol, Ali Torkamani, Pentti Tienari, Tatiana M. Foroud, Bernardino Ghetti, John E. Landers, Mina Ryten, Huw R. Morris, John A. Hardy, Letizia Mazzini, Sandra D'Alfonso, Cristina Moglia, Andrea Calvo, Geidy E. Serrano, Thomas G. Beach, Tanis Ferman, Neill R. Graff-Radford, Bradley F. Boeve, Zbigniew K. Wszolek, Dennis W. Dickson, Adriano Chiò, David A. Bennett, Philip L. De Jager, Owen A. Ross, Clifton L. Dalgard, J. Raphael Gibbs, Bryan J. Traynor, Sonja W. Scholz, Anthony R. Soltis, Coralie Viollet, Gauthaman Sukumar, Camille Alba, Nathaniel Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bacikova, Xijun Zhang, Daniel N. Hupalo, Adelani Adeleye, Matthew D. Wilkerson, Harvey B. Pollard, Ziv Gan-Or, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Antonio Canosa, Adriano Chio, Giancarlo Logroscino, Gabriele Mora, Reijko Krüger, Patrick May, Daniel Alcolea, Jordi Clarimon, Juan Fortea, Isabel Gonzalez-Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pastor, Pascual Sanchez-Juan, Francesca Brett, Dag Aarsland, Safa Al-Sarraj, Johannes Attems, Steve Gentleman, Angela K. Hodges, Seth Love, Ian G. McKeith, Christopher M. Morris, Laura Palmer, Stuart Pickering-Brown, Alan J. Thomas, Claire Troakes, Matthew J. Barrett, Lynn M. Bekris, Kelley Faber, Margaret E. Flanagan, Alison Goate, David S. Goldstein, Horacio Kaufmann, Walter A. Kukull, James B. Leverenz, Grisel Lopez, Qinwen Mao, Eliezer Masliah, Edwin Monuki, Kathy L. Newell, Jose-Alberto Palma, Matthew Perkins, Alan E. Renton, Clemens R. Scherzer, Vikram G. Shakkottai, Ellen Sidransky, Nahid Tayebi, Randy Woltjer, Robert H. Baloh, Robert Bowser, James Broach, William Camu, John Cooper-Knock, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Eva Feldman, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Jonathan D. Glass, Matthew B. Harms, Terry D. Heiman-Patterson, Lilja Jansson, Janine Kirby, Justin Kwan, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel J.L. MacGowan, Nicholas J. Maragakis, Kevin Mouzat, Liisa Myllykangas, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Wim Robberecht, Jeffrey D. Rothstein, Michael Sendtner, Pamela J. Shaw, Katie C. Sidle, Zachary Simmons, Thor Stein, David J. Stone, Pentti J. Tienari, Miko Valori, Philip Van Damme, Vivianna M. Van Deerlin, Ludo Van Den Bosch, Lorne Zinman, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], and Luxembourg Institute of Health - LIH [research center]
- Subjects
amyotrophic lateral sclerosis ,Neurologie [D14] [Sciences de la santé humaine] ,genome-wide association study ,Neurology [D14] [Human health sciences] ,case-control study ,Non-Alzheimer dementia ,resource ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,frontotemporal dementia ,structural variant ,Genetics ,non–Alzheimer's dementia ,Genetics & genetic processes [F10] [Life sciences] ,Lewy body dementia ,Structural variants ,Génétique & processus génétiques [F10] [Sciences du vivant] - Abstract
We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.
- Published
- 2023