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

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

doi:10.1038/s41588-021-00785-3

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.