Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias
Karri Kaivola, Ruth Chia, Jinhui Ding, Memoona Rasheed, Masashi Fujita, Vilas Menon, Ronald L. Walton, Ryan L. Collins, Kimberley J. Billingsley, Harrison Brand, Michael E. Talkowski, Xuefang Zhao, Ramita Dewan, Ali Stark, Anindita Ray, Sultana Solaiman, Pilar Álvarez 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, Anthony R. Soltis, Coralie Viollet, Gauthaman Sukumar, Camille Alba, Nathaniel M. Lott, Elisa McGrath Martinez, Meila Tuck, Jatinder Singh, Dagmar Bačíková, Xijun Zhang, Daniel N. Hupalo, Adelani Adeleye, Matthew D. Wilkerson, Harvey B. Pollard, Clifton L. Dalgard, Sandra E. Black, Ziv Gan‐Or, Julia Keith, Mario Masellis, Ekaterina Rogaeva, Alexis Brice, Suzanne Lesage, Georgia Xiromerisiou, Andrea Calvo, Antonio Canosa, Adriano Chiò, Giancarlo Logroscino, Gabriele Mora, Reijko Krüger, Patrick May, Daniel Alcolea, Jordi Clarimón, Juan Fortea, Isabel González Aramburu, Jon Infante, Carmen Lage, Alberto Lleó, Pau Pástor, Pascual Sánchez‐Juan, Francesca Brett, Dag Aarsland, Safa Al‐Sarraj, Johannes Attems, Steve Gentleman, John Hardy, Angela Hodges, Seth Love, Ian G. McKeith, Christopher M. Morris, Huw R. Morris, Laura Palmer, Stuart Pickering‐Brown, Mina Ryten, Alan Thomas, Claire Troakes, Marilyn S. Albert, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Bradley F. Boeve, Clifton L. Dalgard, Ted M. Dawson, Dennis W. Dickson, Kelley Faber, Tanis Ferman, Luigi Ferrucci, Margaret E. Flanagan, Tatiana Foroud, Bernardino Ghetti, J. Raphael Gibbs
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.