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

By Ruth Chia, Marya S. Sabir, Sara Bandres-Ciga, Sara Saez-Atienzar, Regina H. Reynolds, Emil Gustavsson, Ronald L Walton, Sarah Ahmed, Coralie Viollet, Jinhui Ding, Mary B Makarious, Monica Diez-Fairen, Makayla K. Portley, Zalak Shah, Yevgeniya Abramzon, Dena G. Hernandez, Cornelis Blauwendraat, David J Stone, John Eicher, Laura Parkkinen, Olaf Ansorge, Lorraine Clark, Lawrence S Honig, Karen Marder, Afina 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 Goldstein, Grisel Lopez, Nahid Tayebi, Ellen Sidransky, the Fox Investigation for New Discovery of Biomarkers; The American Genome Center; Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Horacio Kaufmann, Vikram Shakkottai, Matthew Perkins, Kathy L. Newell, Thomas Gasser, Claudia Schulte, Francesco Landi, Erika Salvi, Daniele Cusi, Eliezer Masliah, Ronald C. Kim, Chad A. Caraway, Ed 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 Sanchez-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 J Thomas, Johannes Attems, Christopher M. Morris, Laura Palmer, Seth Love, Claire Troakes, Safa Al-Sarraj, Angela K. Hodges, Dag Aarsland, Gregory Klein, Scott M. Kaiser, Randy Woltjer, Pau Pastor, Lynn M. Bekris, James Leverenz, Lilah M. Besser, Amanda Kuzma, Alan E Renton, Alison M. Goate, David A. Bennett, Clemens R Scherzer, Huw R Morris, Raffaele Ferrari, Diego Albani, Stuart Pickering- Brown, Kelley Faber, Walter Kukull, Estrella Morenas-Rodriguez, Alberto Lleó, Juan Fortea, Daniel Alcolea, Jordi Clarimon, Michael A. Nalls, Luigi Ferrucci, Susan M Resnick, Toshiko Tanaka, Tatiana Foroud, Neill R. Graff-Radford, Zbigniew K. Wszolek, Tanis Ferman, Bradley F. Boeve, John A. Hardy, Eric Topol, Ali Torkamani, Andrew Singleton, Mina Ryten, Dennis Dickson, Adriano Chiò, Owen A. Ross, J. Raphael Gibbs, Clifton L Dalgard, Bryan J. Traynor, Sonja W. Scholz

Posted 06 Jul 2020
bioRxiv DOI: 10.1101/2020.07.06.185066

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 and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition. ### Competing Interest Statement Thomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests.

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