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51. A reference induced pluripotent stem cell line for large-scale collaborative studies

Author

Caroline B. Pantazis, Andrian Yang, Erika Lara, Justin A. McDonough, Cornelis Blauwendraat, Lirong Peng, Hideyuki Oguro, Jitendra Kanaujiya, Jizhong Zou, David Sebesta, Gretchen Pratt, Erin Cross, Jeffrey Blockwick, Philip Buxton, Lauren Kinner-Bibeau, Constance Medura, Christopher Tompkins, Stephen Hughes, Marianita Santiana, Faraz Faghri, Mike A. Nalls, Daniel Vitale, Shannon Ballard, Yue A. Qi, Daniel M. Ramos, Kailyn M. Anderson, Julia Stadler, Priyanka Narayan, Jason Papademetriou, Luke Reilly, Matthew P. Nelson, Sanya Aggarwal, Leah U. Rosen, Peter Kirwan, Venkat Pisupati, Steven L. Coon, Sonja W. Scholz, Theresa Priebe, Miriam Öttl, Jian Dong, Marieke Meijer, Lara J.M. Janssen, Vanessa S. Lourenco, Rik van der Kant, Dennis Crusius, Dominik Paquet, Ana-Caroline Raulin, Guojun Bu, Aaron Held, Brian J. Wainger, Rebecca M.C. Gabriele, Jackie M Casey, Selina Wray, Dad Abu-Bonsrah, Clare L. Parish, Melinda S. Beccari, Don W. Cleveland, Emmy Li, Indigo V.L. Rose, Martin Kampmann, Carles Calatayud Aristoy, Patrik Verstreken, Laurin Heinrich, Max Y. Chen, Birgitt Schüle, Dan Dou, Erika L.F. Holzbaur, Maria Clara Zanellati, Richa Basundra, Mohanish Deshmukh, Sarah Cohen, Richa Khanna, Malavika Raman, Zachary S. Nevin, Madeline Matia, Jonas Van Lent, Vincent Timmerman, Bruce R. Conklin, Katherine Johnson Chase, Ke Zhang, Salome Funes, Daryl A. Bosco, Lena Erlebach, Marc Welzer, Deborah Kronenberg-Versteeg, Guochang Lyu, Ernest Arenas, Elena Coccia, Lily Sarrafha, Tim Ahfeldt, John C. Marioni, William C. Skarnes, Mark R. Cookson, Michael E. Ward, and Florian T. Merkle

Abstract

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate iPSC lines and deeply characterised their genetic properties using whole genome sequencing, their genomic stability upon CRISPR/Cas9-based gene editing, and their phenotypic properties including differentiation to commonly-used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and hundreds of its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.SummaryThe authors of this collaborative study deeply characterized human induced pluripotent stem cell (iPSC) lines to rationally select a clonally-derived cell line that performs well across multiple modalities. KOLF2.1J was identified as a candidate reference cell line based on single-cell analysis of its gene expression in the pluripotent state, whole genome sequencing, genomic stability after highly efficient CRISPR-mediated gene editing, integrity of the p53 pathway, and the efficiency with which it differentiated into multiple target cell populations. Since it is deeply characterized and can be readily acquired, KOLF2.1J is an attractive reference cell line for groups working with iPSCs.Graphical abstract

Published
2021
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52. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2020

53. Accelerating Medicines Partnership: Parkinson’s Disease. Genetic Resource

Author

Andrew B. Singleton, Xianjun Dong, David Vismer, Matt Bookman, Leonie Misquitta, Cornelis Blauwendraat, Mahdiar Sadeghi, Yeajin Song, Sonja W. Scholz, Barry Landin, Hirotaka Iwaki, J. Raphael Gibbs, Clifton L. Dalgard, Mary B. Makarious, Mike A. Nalls, Hampton L. Leonard, Dinesh Kumar, Shameek Biswas, Daniel Vitale, Clemens R. Scherzer, Bradford Casey, and Dena G. Hernandez

Subjects
Oncology, medicine.medical_specialty, education.field_of_study, Parkinson's disease, business.industry, Population, Disease, medicine.disease, LRRK2, Genetic resources, Clinical diagnosis, Internal medicine, medicine, business, education, Genotyping, Cohort study
Abstract

BackgroundWhole-genome sequencing (WGS) data is available from several large studies across a variety of diseases and traits. However, massive storage and computation resources are required to use these data, and, to achieve the sufficient power for discoveries, harmonization of multiple cohorts is critical.ObjectivesThe Accelerating Medicines Partnership Parkinson’s Disease (AMP PD) program has developed a research platform for Parkinson’s disease (PD) which integrates the storage and analysis of WGS data, RNA expression data, and clinical data, harmonized across multiple cohort studies.MethodsThe version 1 release contains WGS data derived from 3,941 participants from 4 cohorts. Samples underwent joint genotyping by the TOPMed Freeze 9 Variant Calling Pipeline. We performed descriptive analyses of these WGS data using the AMP PD platform.ResultsThe clinical diagnosis of participants in version 1 release includes 2,005 idiopathic PD patients, 963 healthy controls, 64 prodromal subjects, 62 clinically diagnosed PD subjects without evidence of dopamine deficit (SWEDD) and 705 participants of genetically enriched cohorts carrying PD risk associated GBA variants or LRRK2 variants in which 304 were affected. We did not observe a significant enrichment of pathogenic variants in the idiopathic PD group, but the polygenic risk score (PRS) was higher in PD both in non-genetically enriched cohorts and genetically enriched cohorts. The population analysis showed a correlation between genetically enriched cohorts and Ashkenazi Jewish ancestry.ConclusionsWe describe the genetic component of the AMP PD platform, a solution to democratise data access and analysis for the PD research community.(d) Financial Disclosure/CoI

Published
2020

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

Author

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

Subjects
0303 health sciences, Lewy body, Disease, Computational biology, Biology, medicine.disease, DNA sequencing, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

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.

Published
2020

55. Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Author

Mary B. Makarious, Andrew B. Singleton, Lasse Pihlstrøm, Mark R. Cookson, Mina Ryten, Alastair J. Noyce, Debra Ehrlich, Ziv Gan-Or, Jonggeol Jeff Kim, Jinhui Ding, Bryan J. Traynor, Hirotaka Iwaki, Cornelis Blauwendraat, Juan A. Botía, Dena G. Hernandez, Matthew Bookman, Ali Torkamani, Monica Diez-Fairen, Sara Saez-Atienzar, Mike A. Nalls, Sonja W. Scholz, Hampton L. Leonard, Sara Bandres-Ciga, Clemens R. Scherzer, Faraz Faghri, and Raphael Gibbs

Subjects
0303 health sciences, Context (language use), Computational biology, Disease, Quantitative trait locus, Biology, 3. Good health, Biological pathway, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Cohort, Polygenic risk score, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological pathways underlying PD using the largest currently available cohorts of genetic data and gene expression data from International Parkinson’s Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership - Parkinson’s disease initiative (AMP-PD), among other sources. We placed these insights into a cellular context. We applied large-scale pathway-specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk in a cohort of 457,110 individuals by focusing on a compilation of 2,199 publicly annotated gene sets representative of curated pathways, of which we nominate 46 pathways associated with PD risk. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data, including 4,331 individuals. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for adult dopaminergic neurons, serotonergic neurons, and radial glia. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of 1,612 PD patients, which revealed 54 connecting networks associated with PD. Our analyses highlight several promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Published
2020

56. Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

Author

John Hardy, Günter U. Höglinger, Olga Pletnikova, Janice L. Holton, Tamas Revesz, Sonja W. Scholz, Zane Jaunmuktane, Edwin Jabbari, J. Raphael Gibbs, Raffaele Ferrari, Alexander Pantelyat, Kieren Allinson, Gesine Respondek, Maryam Shoai, Dennis W. Dickson, Coralie Viollet, David Murphy, Alistair Church, Clifton L. Dalgard, Mina Ryten, Bryan J. Traynor, Rebecca R. Valentino, Alexander Gerhard, Nicola Pavese, Manuela Tan, Andrew J. Lees, David J. Burn, James B. Rowe, Huw R. Morris, Christopher Kobylecki, Adam L. Boxer, Thomas T. Warner, Juan C. Troncoso, Owen A. Ross, Michele T.M. Hu, Regina H. Reynolds, Steve M. Gentleman, Kin Y. Mok, Jinhui Ding, P. Nigel Leigh, Safa Al-Sarraj, Ruth Chia, and Mark R. Cookson

Subjects
Regulation of gene expression, 0303 health sciences, Disease progression, Locus (genetics), Biology, Bioinformatics, medicine.disease, LRRK2, Motor symptoms, Progressive supranuclear palsy, nervous system diseases, 03 medical and health sciences, 0302 clinical medicine, Proteostasis, medicine, Tauopathy, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.

Published
2020
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57. Clinical utility of whole-genome sequencing in a large ALS cohort

Author

Andrea Calvo, Lucia Corrado, Ruth Chia, Jinhui Ding, Letizia Mazzini, Sandra D'Alfonso, Antonio Canosa, Cristina Moglia, Maurizio Grassano, Bryan J. Traynor, Clifton L. Dalgard, Fabiola De Marchi, Umberto Manera, Adriano Chiò, Maura Brunetti, Rosario Vasta, Raphael Gibbs, and Sonja W. Scholz

Subjects
Whole genome sequencing, Neurology, Cohort, Neurology (clinical), Computational biology, Biology
Published
2021

58. Conjugal multiple system atrophy: Rethinking numbers of probability

Author

Wolfgang Mitterer, Gregor K. Wenning, Margot Fodor, Sonja W. Scholz, Johannes G. Weiss, and Lukas Lanser

Subjects
Alpha-synuclein, Parkinson Disease, Multiple System Atrophy, Biology, medicine.disease, law.invention, chemistry.chemical_compound, Transmission (mechanics), Atrophy, Neurology, chemistry, law, Cerebellum, alpha-Synuclein, medicine, Humans, Neurology (clinical), Geriatrics and Gerontology, Neuroscience, Probability
Published
2020

59. ARSA variants in α-synucleinopathies

Author

Cornelis Blauwendraat, Henry Houlden, Monica Diez-Fairen, Ziv Gan-Or, Lynne Krohn, Lasse Pihlstrøm, Mary B. Makarious, Sara Bandres-Ciga, Sonja W. Scholz, and Jinhui Ding

Subjects
Alpha-synuclein, Synucleinopathies, 0303 health sciences, business.industry, Extramural, Cerebroside-sulfatase, Parkinson Disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Biochemistry, alpha-Synuclein, Medicine, Humans, Neurology (clinical), business, Letters to the Editor, 030217 neurology & neurosurgery, Cerebroside-Sulfatase, 030304 developmental biology, Molecular Chaperones
Published
2019

60. Predicting Alzheimer’s disease progression trajectory and clinical subtypes using machine learning

Author

Mary B. Makarious, Hirotaka Iwaki, Faraz Faghri, Lana Sargent, Andrew B. Singleton, Anant Dadu, Hampton L. Leonard, Mike A. Nalls, Rachneet Kaur, Vipul K. Satone, Roy H. Campbell, Sonja W. Scholz, and Ali Daneshmand

Subjects
business.industry, Disease progression, Cognition, Disease, Machine learning, computer.software_genre, Confidence interval, Clinical trial, Early prediction, Etiology, Medicine, Personalized medicine, Artificial intelligence, business, computer
Abstract

BackgroundAlzheimer’s disease (AD) is a common, age-related, neurodegenerative disease that impairs a person’s ability to perform day-to-day activities. Diagnosing AD is challenging, especially in the early stages. Many patients still go undiagnosed, partly due to the complex heterogeneity in disease progression. This highlights a need for early prediction of the disease course to assist its treatment and tailor therapy options to the disease progression rate. Recent developments in machine learning techniques provide the potential to not only predict disease progression and trajectory of AD but also to classify the disease into different etiological subtypes.Methods and findingsThe work shown here clusters participants in distinct and multifaceted progression subgroups of AD and discusses an approach to predict the progression rate from baseline diagnosis. We observed that the myriad of clinically reported symptoms summarized in the proposed AD progression space corresponds directly with memory and cognitive measures, which are routinely used to monitor disease onset and progression. Our analysis demonstrated accurate prediction of disease progression after four years from the first 12 months of post-diagnosis clinical data (Area Under the Curve of 0.96 (95% confidence interval (CI), 0.92-1.0), 0.81 (95% CI, 0.74-0.88) and 0.98 (95% CI, 0.96-1.0) for slow, moderate and fast progression rate patients respectively). Further, we explored the long short-term memory (LSTM) neural networks to predict the trajectory of an individual patient’s progression.ConclusionThe machine learning techniques presented in this study may assist providers in identifying different progression rates and trajectories in the early stages of the disease, hence allowing for more efficient and personalized healthcare deliveries. With additional information about the progression rate of AD at hand, providers may further individualize the treatment plans. The predictive tests discussed in this study not only allow for early AD diagnosis but also facilitate the characterization of distinct AD subtypes relating to trajectories of disease progression. These findings are a crucial step forward for early disease detection. These models can be used to design improved clinical trials for AD research.

Published
2019

61. Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls across Multiple Cohorts

Author

Mary Alice Allnutt, Juan C. Troncoso, Susan M. Resnick, Philip L. De Jager, Steven Jacobson, Sarah M. Connor, Kory R. Johnson, Olga Pletnikova, Marilyn S. Albert, David A. Bennett, and Sonja W. Scholz

Subjects
0301 basic medicine, Male, viruses, Herpesvirus 6, Human, Disease, medicine.disease_cause, Viral infection, Virus, Article, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, biology, Sequence Analysis, RNA, General Neuroscience, RNA, virus diseases, Brain, Cytomegalovirus, Area of interest, Sequence Analysis, DNA, biology.organism_classification, Virology, 030104 developmental biology, chemistry, Case-Control Studies, Human herpesvirus 6, Female, 030217 neurology & neurosurgery, DNA
Abstract

The interplay between viral infection and Alzheimer's disease (AD) has long been an area of interest, but proving causality has been elusive. Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus 6 (HHV-6) in particular, in AD. We screened for HHV-6 detection across three independent AD brain repositories using (1) RNA sequencing (RNA-seq) datasets and (2) DNA samples extracted from AD and non-AD control brains. The RNA-seq data were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses, whereas DNA samples were probed for PCR reactivity to HHV-6A and HHV-6B. HHV-6 demonstrated little specificity to AD brains over controls by either method, whereas other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), were detected at comparable levels. These direct methods of viral detection do not suggest an association between HHV-6 and AD.

Published
2019

62. Mutations in the SPTLC1 gene are a cause of juvenile amyotrophic lateral sclerosis that may be amenable to serine supplementation

Author

Pentti J. Tienari, Al-Saif H, Ruth Chia, Jinhui Ding, Janel O. Johnson, Claire Troakes, Maura Brunetti, Emily Bonkowski, Mark R. Cookson, Gabriele Mora, Pamela J. Shaw, Adriano Chiò, Simon Topp, Mike A. Nalls, Ammar Al-Chalabi, Bryan J. Traynor, Christopher Shaw, Carol Dobson-Stone, Natalie Landeck, Leigh F, Nada Alahmady, Nathan A. Smith, Olga Pletnikova, David J. Stone, Ian P. Blair, Robert H. Brown, Chang Ij, Thomas O. Crawford, Silani, Marc Gotkine, Alfredo Iacoangeli, Juan C. Troncoso, Karen E. Morrison, Ian A. Glass, Sarah A. Ahmed, Gibbs, Alan E. Renton, Marya S. Sabir, Aleksey Shatunov, Sonja W. Scholz, Li R, Bradley N. Smith, John Landers, Ravindran Kumaran, John B.J. Kwok, Ashley R. Jones, Andrea Calvo, Danny E. Miller, C. Gellera, Faraz Faghri, Hannah A. Pliner, England Bk, Nicola Ticozzi, Yevgeniya Abramzon, Al Khleifat A, Seth J. Perlman, and Clifton L. Dalgard

Subjects
0303 health sciences, Mutation, business.industry, Serine C-palmitoyltransferase, Motor neuron, medicine.disease, medicine.disease_cause, 3. Good health, Pathogenesis, Serine, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Cancer research, Amyotrophic lateral sclerosis, SPTLC1, business, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A . Using exome sequencing, we identified a de novo variant in SPTLC1 resulting in a p.Ala20Ser amino acid change in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS) and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. A second case of juvenile-onset ALS arising again from a p.Ala20Ser mutation was later identified, confirming the association of SPTLC1 with this form of motor neuron disease. We also found SPTLC1 mutations in 0.34% of 5,607 ALS cases, and immunohistochemically confirmed the expression of SPTLC1 in spinal cord motor neurons, supporting their role in the pathogenesis of this fatal neurological disease. We corrected the toxicity of deoxymethyl-sphinganine in HEK293FT cells using L-serine supplementation. Our data broaden the phenotype associated with SPTLC1 and suggest that nutritional supplementation with serine may be beneficial if instituted at an early stage among patients carrying mutations in SPTLC1 .

Published
2019

63. A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease

Author

Shahram Bahrami, Gregor K. Wenning, J. Raphael Gibbs, Antonio Heras-Garvin, Sonja W. Scholz, Stefan Schreiber, Wassilios G. Meissner, John Hardy, Andrew B. Singleton, Monia B. Hammer, Markus M. Nöthen, Manu Sharma, Olivier Rascol, Ole A. Andreassen, Cornelis Blauwendraat, Oleksandr Frei, Martina Müller-Nurasyid, Ashwin Ashok Kumar Sreelatha, Andreas Arnold, Thomas Gasser, David Ellinghaus, Carsten Oliver Schmidt, Jinhui Ding, Nadia Stefanova, Andre Franke, Kevin S. O’Connell, Anne Pavy-Le Traon, Alexey A. Shadrin, Wolfgang Lieb, Georg Homuth, Mary B. Makarious, Christian Gieger, Per Hoffmann, Alexandra Foubert-Samier, Sören Mucha, and Henry Houlden

Subjects
Genetics, 0303 health sciences, Methylation, Heritability, Biology, medicine.disease, Genome, Inflammatory bowel disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Immune system, nervous system, stomatognathic system, Genetic Pleiotropy, medicine, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

Published
2019
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64. MAPT p.V363I mutation: A rare cause of corticobasal degeneration

Author

Sarah A. Ahmed, Jinhui Ding, Sonja W. Scholz, Edwin Jabbari, Huw R. Morris, Pau Pastor, Olga Pletnikova, Ellen Gelpi, Claudia Schulte, Ankur Butala, Marya S. Sabir, Monica Diez Fairen, Thomas Gasser, Christopher Morris, Juan C. Troncoso, Lourdes Ispierto, and Alexander Pantelyat

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Tau protein, Genetic analysis, 03 medical and health sciences, 0302 clinical medicine, Aphasia, medicine, Corticobasal degeneration, ddc:610, Genotyping, Genetics (clinical), biology, business.industry, Parkinsonism, medicine.disease, 3. Good health, 030104 developmental biology, Mutation (genetic algorithm), biology.protein, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Rare disease
Abstract

ObjectivePatients with corticobasal syndrome (CBS) present with heterogeneous clinical features, including asymmetric parkinsonism, dyspraxia, aphasia, and cognitive impairment; to better understand the genetic etiology of this rare disease, we undertook a genetic analysis of microtubule-associated protein tau (MAPT).MethodsWe performed a genetic evaluation of MAPT mutations in 826 neurologically healthy controls and 173 cases with CBS using the Illumina NeuroChip genotyping array.ResultsWe identified 2 patients with CBS heterozygous for a rare mutation in MAPT (p.V363I) that is located in the highly conserved microtubule-binding domain. One patient was pathologically confirmed and demonstrated extensive 4-repeat-tau-positive thread pathology, achromatic neurons, and astrocytic plaques consistent with corticobasal degeneration (CBD).ConclusionsWe report 2 CBS cases carrying the rare p.V363I MAPT mutation, one of which was pathologically confirmed as CBD. Our findings support the notion that this rare coding change is pathogenic.

Published
2019

65. A comprehensive screening of copy number variability in dementia with Lewy bodies

Author

Sonja W. Scholz, Pentti J. Tienari, Dena G. Hernandez, Elisabet Londos, Alberto Lleó, Imelda Barber, Jose Bras, Owen A. Ross, Tanis J. Ferman, Tatiana Orme, Juan C. Troncoso, Andrew B. Singleton, John D. Eicher, John Hardy, Karen Marder, Tammaryn Lashley, Douglas Galasko, Liisa Myllykangas, Ted M. Dawson, Eliezer Masliah, David M. A. Mann, Ekaterina Rogaeva, Stuart Pickering-Brown, Monica Diez-Fairen, Claire Troakes, Peter St George-Hyslop, Nigel J. Cairns, Dennis W. Dickson, Lee Darwent, Thomas G. Beach, David J. Stone, Olga Pletnikova, Glenda M. Halliday, Jordi Clarimón, John Q. Trojanowski, Anne Braae, Claire E. Shepherd, Pau Pastor, Geidy E. Serrano, Susana Carmona, Minna Oinas, Andrew J. Lees, Afina W. Lemstra, Miquel Aguilar, Laura Parkkinen, Rita Guerreiro, Estrella Morenas-Rodríguez, Janice L. Holton, Olaf Ansorge, Tamas Revesz, Vivianna M. Van Deerlin, Neill R. Graff-Radford, Safa Al-Sarraj, Kristelle Brown, Valentina Escott-Price, Suzanne Lesage, Lawrence S. Honig, Celia Kun-Rodrigues, John C. Morris, Ronald C. Petersen, Henrik Zetterberg, Kevin Morgan, Brad F. Boeve, Lorraine N. Clark, Isabel Santana, Yaroslau Compta, Liana S. Rosenthal, Michael G. Heckman, Neurology, Amsterdam Neuroscience - Neurodegeneration, Department of Neurosciences, Research Programme for Molecular Neurology, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Department of Pathology, Liisa Tellervo Myllykangas / Principal Investigator, Medicum, Neurokirurgian yksikkö, and HUS Neurocenter

Subjects
0301 basic medicine, Male, Aging, Candidate gene, ALPHA-SYNUCLEIN, Dementia with Lewy bodies, Genome-wide association study, Variações do Número de Cópias de DNA, 3124 Neurology and psychiatry, 0302 clinical medicine, RARE, genetics [Lewy Body Disease], genetics [Adaptor Proteins, Signal Transducing], PURINE METABOLISM, MAPT GENE, MAPT, GLUCOCEREBROSIDASE MUTATIONS, Genome-wide, Copy-number variation, genetics [Genetic Predisposition to Disease], SNAPSHOT GENETICS, SYNUCLEIN GENE DUPLICATION, Aged, 80 and over, Oncogene Proteins, Genome, General Neuroscience, 3. Good health, ALZHEIMERS-DISEASE, genetics [Membrane Proteins], genetics [Polymorphism, Single Nucleotide], Medical genetics, Female, Lewy Body Disease, medicine.medical_specialty, Doença por Corpos de Lewy, DNA Copy Number Variations, genetics [DNA Copy Number Variations], Computational biology, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic variability, GENOME-WIDE ASSOCIATION, Genotyping, PARKINSON-DISEASE, Genetic association, Adaptor Proteins, Signal Transducing, Copy number variants, Membrane Proteins, genetics [Oncogene Proteins], medicine.disease, nervous system diseases, Proteínas Oncogénicas, 030104 developmental biology, SNCA, Neurology (clinical), Geriatrics and Gerontology, Predisposição Genética para Doença, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk. (C) 2019 Elsevier Inc. All rights reserved.

Published
2019

66. Human Herpesvirus-6 (HHV-6) Detection in Alzheimer's Disease Cases and Controls Across Multiple Cohorts

Author

David A. Bennett, Kory R. Johnson, Sonja W. Scholz, Steven Jacobson, Sarah M. Connor, Mary Alice Allnutt, Olga Pletnikova, Juan C. Troncoso, Susan M. Resnick, Philip L. De Jager, and Marilyn S. Albert

Subjects
viruses, virus diseases, Cytomegalovirus, Disease, Area of interest, Biology, medicine.disease_cause, biology.organism_classification, Viral infection, Virology, Virus, chemistry.chemical_compound, chemistry, medicine, Human herpesvirus 6, DNA
Abstract

The interplay between viral infection and Alzheimer’s disease (AD) has long been an area of interest but proving causality has been elusive. Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus-6 (HHV-6) in particular, in AD. We screened for HHV-6 detection across three independent AD brain repositories, using (1) RNAseq datasets and (2) DNA samples extracted from AD and non-AD control brains. The RNAseq data were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses, while DNA samples were probed for PCR reactivity to HHV-6A and HHV-6B. HHV-6 demonstrated little specificity to AD brains over controls by either method, while other viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were detected at comparable levels. These direct methods of viral detection do not suggest a strong association between HHV-6 and AD.

Published
2019

67. A critique of the second consensus criteria for multiple system atrophy

Author

Anthony E. Lang, Glenda M. Halliday, Thomas Klockgether, Klaus Seppi, Gregor K. Wenning, Sonja W. Scholz, Lucy Norcliffe Kaufmann, Iva Stankovic, Joaquim J. Ferreira, Günter U. Höglinger, Vladimir S. Kostic, Shoji Tsuji, Angelo Antonini, Niall Quinn, Horacio Kaufmann, Jose-Alberto Palma, Roy Freeman, Alessandra Fanciulli, Maria Stamelou, Phillip A. Low, Maria Teresa Pellecchia, Christopher J. Mathias, Daniela Berg, Wolfgang Singer, Johannes Levin, Wassillios G. Meissner, Ryuji Sakakibara, Elizabeth A. Coon, Jalesh N. Panicker, Jeremy D. Schmahmann, Luca Vignatelli, Werner Poewe, Florian Krismer, Pietro Cortelli, Eduardo Tolosa, Valeria Iodice, Repositório da Universidade de Lisboa, Stankovic I., Quinn N., Vignatelli L., Antonini A., Berg D., Coon E., Cortelli P., Fanciulli A., Ferreira J.J., Freeman R., Halliday G., Hoglinger G.U., Iodice V., Kaufmann H., Klockgether T., Kostic V., Krismer F., Lang A., Levin J., Low P., Mathias C., Meissner W.G., Kaufmann L.N., Palma J.-A., Panicker J.N., Pellecchia M.T., Sakakibara R., Schmahmann J., Scholz S.W., Singer W., Stamelou M., Tolosa E., Tsuji S., Seppi K., Poewe W., and Wenning G.K.

Subjects
Pediatrics, medicine.medical_specialty, Consensus, health care facilities, manpower, and services, Treatment outcome, education, MEDLINE, Consensus criteria, therapeutic use [Levodopa], Article, Levodopa, 03 medical and health sciences, 0302 clinical medicine, Atrophy, stomatognathic system, 030225 pediatrics, mental disorders, MSA, Medicine, Humans, Genetic Predisposition to Disease, ddc:610, health care economics and organizations, business.industry, Multiple System Atrophy, medicine.disease, multiple system atrophy criteria, 3. Good health, nervous system diseases, Treatment Outcome, diagnosis [Multiple System Atrophy], nervous system, Neurology, drug therapy [Multiple System Atrophy], genetics [Multiple System Atrophy], Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

© 2019 International Parkinson and Movement Disorder Society, Multiple system atrophy (MSA) is an adult-onset progressive neurodegenerative disorder that manifests clinically with autonomic failure, parkinsonism, and ataxia in any combination. Oligodendroglial cytoplasmatic inclusions consisting of misfolded α-synuclein are a pathological hallmark of disease. The clinical diagnosis of MSA is typically delayed as a result of incomplete or nonspecific manifestations during early disease stages. Quinn first published diagnostic criteria for MSA in 1989. Since then, the first consensus criteria in 1998 and their revision in 2008 have been widely accepted as diagnostic guidelines for MSA.

Published
2019

69. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Author

Sonja W. Scholz, Dena G. Hernandez, Juan C. Troncoso, David J. Stone, Alexander Pantelyat, Ted M. Dawson, Olga Pletnikova, J. Raphael Gibbs, John Hardy, Barbara J. Crain, Christopher Letson, Argye E. Hillis, Liana S. Rosenthal, Andrew B. Singleton, Marilyn S. Albert, Joshua T. Geiger, and Jinhui Ding

Subjects
Lewy Body Disease, Male, Exome sequencing, 0301 basic medicine, Dementia with Lewy bodies, Biology, Article, lcsh:RC321-571, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Missense mutation, Dementia, Genetic Predisposition to Disease, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Allele frequency, Aged, Genetic testing, Aged, 80 and over, PSEN1, Genetics, Alzheimer dementia, Lewy body, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, 030104 developmental biology, Neurology, Mutation, North America, Mutation (genetic algorithm), Female, Lewy Bodies, GBA, Lewy body dementia, 030217 neurology & neurosurgery
Abstract

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value

Published
2016

70. Heritability and genetic variance of dementia with Lewy bodies

Author

Rita Guerreiro, Jose Bras, Tanis J. Ferman, Stuart Pickering-Brown, Susana Carmona, Laura Parkkinen, Andrew B. Singleton, Glenda M. Halliday, Jordi Clarimón, Lee Darwent, Olaf Ansorge, Monica Diez-Fairen, Karen Marder, Geidy E. Serrano, David M. A. Mann, Thomas G. Beach, Michael G. Heckman, Andrew J. Lees, Miquel Aguilar, Liisa Myllykangas, Tatiana Orme, Henrik Zetterberg, Alberto Lleó, Lorraine N. Clark, Estrella Morenas-Rodriguez, Claire E. Shepherd, Ekaterina Rogaeva, Elisabet Londos, Douglas Galasko, Isabel Santana, Nadia Dehghani, Kevin Morgan, Eliezer Masliah, Imelda Barber, John D. Eicher, Ronald C. Petersen, Brad F. Boeve, John Hardy, Claire Troakes, Joao Luis Neto, Celia Kun-Rodrigues, Peter St George-Hyslop, Dennis W. Dickson, Janice L. Holton, Pentti J. Tienari, Minna Oinas, Olga Pletnikova, Afina W. Lemstra, John Q. Trojanowski, John C. Morris, Liana S. Rosenthal, Anne Braae, Dena G. Hernandez, Nigel J. Cairns, Pau Pastor, David J. Stone, Juan C. Troncoso, Ted M. Dawson, Owen A. Ross, Tammaryn Lashley, Tamas Revesz, Yaroslau Compta, Sonja W. Scholz, Neill R. Graff-Radford, Safa Al-Sarraj, Vivianna M. Van Deerlin, Kristelle Brown, Valentina Escott-Price, Suzanne Lesage, Lawrence S. Honig, HUS Neurocenter, Department of Neurosciences, Neurologian yksikkö, Research Programs Unit, STEMM - Stem Cells and Metabolism Research Program, Department of Pathology, Helsinki University Hospital Area, Neurokirurgian yksikkö, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Lewy Body Disease, 0301 basic medicine, Genetic correlation, Linkage disequilibrium, LOCI, Genome-wide association study, Biology, Article, 3124 Neurology and psychiatry, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, genetics [Lewy Body Disease], Missing heritability problem, MISSING HERITABILITY, ddc:570, Databases, Genetic, Genetic variation, mental disorders, medicine, Humans, Genetic Predisposition to Disease, POLYGENIC RISK, Genetic variability, GENOME-WIDE ASSOCIATION, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Genetic variance, METAANALYSIS, 030304 developmental biology, Genetics, ARCHITECTURE, 0303 health sciences, Dementia with Lewy bodies, 3112 Neurosciences, Genetic Variation, Heritability, Explained variation, medicine.disease, 3. Good health, ALZHEIMERS-DISEASE, 030104 developmental biology, Neurology, Dementia, Lewy bodies, 030217 neurology & neurosurgery
Abstract

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson’s disease (PD) or Alzheimer’s disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Published
2018
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71. Parkinson disease age of onset GWAS: defining heritability, genetic loci and a-synuclein mechanisms

Author

Joseph Jankovic, Jean-Christophe Corvol, J. Raphael Gibbs, Alexis Brice, Pentti J. Tienari, Rainer von Coelln, Kari Majamaa, Andrew B. Singleton, Mathias Toft, Johan Marinus, Ziv Gan-Or, Javier Simón-Sánchez, Peter Heutink, Lasse Pihlstrøm, Alastair J. Noyce, Thomas Gasser, Lisa M. Shulman, Hirotaka Iwaki, Manuela Tan, John Hardy, Jacobus J. van Hilten, Joshua M. Shulman, Suzanne Lesage, Dena G. Hernandez, Cornelis Blauwendraat, Jacob Gratten, Hampton L. Leonard, Manu Sharma, Ari Siitonen, David A. Hinds, Karl Heilbron, Peter M. Visscher, Lynne Krohn, Mike A. Nalls, Sara Bandres-Ciga, Huw R. Morris, Costanza L. Vallerga, Donald G. Grosset, N Wood, Sonja W. Scholz, and Claudia Schulte

Subjects
Genetics, 0303 health sciences, Locus (genetics), Genome-wide association study, Heritability, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Synuclein, Genetic variability, Age of onset, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Increasing evidence supports an extensive and complex genetic contribution to Parkinson’s disease (PD). Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age of onset are largely unknown. Here we performed an age of onset GWAS based on 28,568 PD cases. We estimated that the heritability of PD age of onset due to common genetic variation was ~0.11, lower than the overall heritability of risk for PD (~0.27) likely in part because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni corrected significant effect at other known PD risk loci, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. In addition, we identified that GBA coding variant carriers had an earlier age of onset compared to non-carriers. Notably, SNCA, TMEM175, SCARB2, BAG3 and GBA have all been shown to either directly influence alpha-synuclein aggregation or are implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci such as GCH1, MAPT and RAB7L1/NUCKS1 (PARK16) did not show a significant effect on age of onset of PD. While for some loci, this may be a measure of power, this is clearly not the case for the MAPT locus; thus genetic variability at this locus influences whether but not when an individual develops disease. We believe this is an important mechanistic and therapeutic distinction. Furthermore, these data support a model in which alpha-synuclein and lysosomal mechanisms impact not only PD risk but also age of disease onset and highlights that therapies that target alpha-synuclein aggregation are more likely to be disease-modifying than therapies targeting other pathways.

Published
2018

72. Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Author

Sonja W. Scholz, Alastair J. Noyce, Claudia Schulte, Pentti J. Tienari, Huw R. Morris, Karl Heilbron, Angli Xue, Jean-Christophe Corvol, Manuela Tan, N Wood, Dena G. Hernandez, Sara Bandres-Ciga, Lisa M. Shulman, Rainer von Coelln, Faraz Faghri, Andrew B. Singleton, Diana Chang, Demis A. Kia, Jian Yang, John Hardy, Jose Bras, Peter M. Visscher, Lynne Krohn, J. Raphael Gibbs, Tushar Bangale, Mike A. Nalls, Alexis Brice, Hirotaka Iwaki, Cornelis Blauwendraat, Lasse Pihlstrøm, Jacob Gratten, Joseph Jankovic, Ole A. Andreassen, Javier Simón-Sánchez, Kari Majamaa, Hampton L. Leonard, Ziv Gan-Or, Thomas Gasser, Juan A. Botía, Maria Martinez, Costanza L. Vallerga, Robert R. Graham, Joshua M. Shulman, Suzanne Lesage, David A. Hinds, Ari Siitonen, Mathias Toft, Manu Sharma, Emily Young, Peter Heutink, and Margaret Sutherland

Subjects
Genetics, 0303 health sciences, Single-nucleotide polymorphism, Context (language use), Disease, Biology, Biobank, Causality, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

Published
2018
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73. LRP10 in α-synucleinopathies

Author

Demis A Kia, Marya S Sabir, Sarah Ahmed, Joanne Trinh, Sara Bandres-Ciga, Alastair J Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Manuela Tan, Henry Houlden, Huw R Morris, Helene Plun-Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, Jose Bras, John Quinn, Kin Y Mok, Kerri J. Kinghorn, Kimberley Billingsley, Nicholas W Wood, Patrick Lewis, Sebastian Schreglmann, Rita Guerreiro, Ruth Lovering, Lea R'Bibo, Mie Rizig, Mina Ryten, Sebastian Guelfi, Valentina Escott-Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean-Christophe Corvol, Maria Martinez, Claudia Schulte, Kathrin Brockmann, Javier Simón-Sánchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Aude Nicolas, Mark R Cookson, Cornelis Blauwendraat, David W. Craig, Faraz Faghri, Raphael J. Gibbs, Dena G Hernandez, Kendall Van Keuren-Jensen, Joshua M. Shulman, Hirotaka Iwaki, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Steven Lubbe, Steven Finkbeiner, Niccolo E. Mencacci, Codrin Lungu, Andrew B Singleton, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan-Or, Guy A. Rouleau, Jacobus J van Hilten, Johan Marinus, Astrid D. Adarmes-Gómez, Miquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Francisco J. Barrero, Jesús A. Bergareche Yarza, Inmaculada Bernal-Bernal, Marta Blazquez, Marta Bonilla-Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza-Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Jordi Clarimón, Monica Diez-Farien, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Mario Ezquerra, Cici Feliz, Manel Fernández, Rubén Fernández-Santiago, Ciara Garcia, Pedro García-Ruiz, Pilar Gómez-Garre, Maria Jose Gomez Heredia, Isabel Gonzalez-Aramburu, Ana Gorostidi Pagola, Janet Hoenicka, Jon Infante, Silvia Jesús, Adriano Jimenez-Escrig, Jaime Kulisevsky, Miguel A. Labrador-Espinosa, Jose L. Lopez-Sendon, Adolfo López de Munain Arregui, Daniel Macias, Irene Martínez Torres, Juan Marín, Maria Jose Marti, Juan Carlos Martínez- Castrillo, Carlota Méndez-del-Barrio, Manuel Menéndez González, Marina Mata, Adolfo Mínguez, Pablo Mir, Elisabet Mondragon Rezola, Esteban Muñoz, Javier Pagonabarraga, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Javier Ruiz-Martínez, Clara Ruz, Antonio Sanchez Rodriguez, María Sierra, Esther Suarez-Sanmartin, Cesar Tabernero, Juan Pablo Tartari, Cristina Tejera-Parrado, Eduard Tolosa, Francesc Valldeoriola, Laura Vargas-González, Lydia Vela, Francisco Vives, Alexander Zimprich, Lasse Pihlstrom, Mathias Toft, Sulev Koks, Pille Taba, and Sharon Hassin-Baer

Subjects
Lewy Body Disease, Genetic Linkage, Humans, Dementia, Lewy Bodies, Parkinson Disease, Neurology (clinical)
Published
2018

74. O5‐04‐01: A RARE GENETIC VARIANT IN THE PLCG2 GENE IS ASSOCIATED WITH A REDUCED RISK OF ALL MAJOR TYPES OF DEMENTIA AND AN INCREASED RISK TO REACH AN EXTREMELY OLD AGE

Author

Alfredo Ramirez, Iris E. Jansen, Javier Simón-Sánchez, Estrella Morenas-Rodríguez, Afina W. Lemstra, Carmen Lage, Marc Hulsman, Pascual Sánchez-Juan, Sven J. van der Lee, Jordi Clarimón, Erik B. van den Akker, Juan Fortea, Sonja W. Scholz, Marcel J. T. Reinders, Najada Stringa, Philip Scheltens, Natasja M. van Schoor, Modifying Factors in Fronto-Temporal Dementia Investigators, Ignacio Illán-Gala, Eloy Rodríguez, Henne Holstege, Eline Slagboom, Amit Kawalia, Martijn Huisman, Yolande A.L. Pijnenburg, Wiesje M. Flier, Agustín Ruiz, Alberto Lleó, Isabel Hernández, Maria Carolina Dalmasso, Cornelis Blauwendraat, Peter Heutink, and Olga Pletnikova

Subjects
Pediatrics, medicine.medical_specialty, Reduced risk, Epidemiology, business.industry, Health Policy, Genetic variants, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Increased risk, Developmental Neuroscience, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, business, Gene, PLCG2
Published
2018

75. Predicting onset, progression, and clinical subtypes of Parkinson disease using machine learning

Author

Leonard H, Mike A. Nalls, Andrew B. Singleton, Roy H. Campbell, Sayed Hadi Hashemi, Sonja W. Scholz, and Faraz Faghri

Subjects
business.industry, Clinical study design, Disease progression, Disease, Patient counseling, Machine learning, computer.software_genre, 01 natural sciences, 3. Good health, Unmet needs, Clinical trial, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Text mining, Cohort, Medicine, Artificial intelligence, 0101 mathematics, business, computer, 030217 neurology & neurosurgery
Abstract

BackgroundThe clinical manifestations of Parkinson disease are characterized by heterogeneity in age at onset, disease duration, rate of progression, and constellation of motor versus nonmotor features. Due to these variable presentations, counseling of patients about their individual risks and prognosis is limited. There is an unmet need for predictive tests that facilitate early detection and characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. The emergence of machine learning to detect hidden patterns in complex, multi-dimensional datasets provides unparalleled opportunities to address this critical need.Methods and FindingsWe used unsupervised and supervised machine learning approaches for subtype identification and prediction. We used machine learning methods on comprehensive, longitudinal clinical data from the Parkinson Disease Progression Marker Initiative (PPMI) (n=328 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson Disease Biomarker Program (PDBP) (n=112 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate and fast disease progressors. We achieved highly accurate projections of disease progression four years after initial diagnosis with an average Area Under the Curve of 0.93 (95% CI: 0.96 ± 0.01 for PDvec1, 0.87 ± 0.03 for PDvec2, and 0.96 ± 0.02 for PDvec3). We have demonstrated robust replication of these findings in the independent validation cohort.ConclusionsThese data-driven results enable clinicians to deconstruct the heterogeneity within their patient cohorts. This knowledge could have immediate implications for clinical trials by improving the detection of significant clinical outcomes that might have been masked by cohort heterogeneity. We anticipate that machine learning models will improve patient counseling, clinical trial design, allocation of healthcare resources and ultimately individualized clinical care.

Published
2018

76. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018

77. A Nonsynonymous Mutation in PLCG2 Reduces the Risk of Alzheimer's Disease, Dementia with Lewy-Bodies and Frontotemporal Dementia, and Increases the Likelihood of Longevity

Author

Bart N.M. van Berckel, Begoña Indakoetxea, Estrella Morenas-Rodríguez, Cornelis Blauwendraat, Christopher Morris, Patrick F. Chinnery, Iris E. Jansen, Danielle Posthuma, Eliezer Masliah, Ingmar Skoog, Heinz Wiendl, Jordi Clarimón, Adela Orellana, Carmen Lage, Neill R. Graff-Radford, Monica Diez-Fairen, Michael Wagner, Rosa Rademakers, Tanis J. Ferman, Daniel Alcolea, Henne Holstege, Zbigniew K. Wszolek, Alfredo Ramirez, Marcel J. T. Reinders, Itziar de Rojas, Kristel R. van Eijk, Erik B. van den Akker, Bradley F. Boeve, Jay A. van Gerpen, Marian Beekman, Agustín Ruiz, Jeanne E. Savage, Modifying factors in Fronto-Temporal Dementia, James W. Ironside, Najada Stringa, Ronald C. Petersen, Lluís Tárraga, Minerva M. Carrasquillo, Adolfo López de Munain, Pascual Sanchez-Juan, Fermin Moreno, Martin Scherer, Afina W. Lemstra, Giovanni Coppola, Henrik Zetterberg, RiMod-FTD Rsk, Nilufer Ertekin-Taner, Ignacio Illán-Gala, Owen A. Ross, Thorkild Ingvor Arrild Sørensen, Alexander Pantelyat, Eline Slagboom, Wiesje M. van der Flier, Till F. M. Andlauer, Amit Kawalia, Bernard Jeune, Wolfgang Maier, Sonia Moreno-Grau, Sven J. van der Lee, Olivia J. Conway, Mariet Allen, Marianne Nygaard, Marc Hulsman, Alberto Lleó, Uwe K. Zettl, Ellen A. Nohr, Philip Scheltens, Jonas Mengel-From, Luca Kleineidam, Yolande A.L. Pijnenburg, Samantha L. Strickland, Isabel Hernández, Olga Pletnikova, Niccolò Tesi, Michael J. Keogh, Juan C. Troncoso, Natasja M. van Schoor, Steffi G. Riedel-Heller, Wei Wei, Oriol Dols-Icardo, David S. Knopman, Ryan J. Uitti, Pau Pastor, Nina Beker, Javier Simón-Sánchez, Kaare Christensen, Anna Zettergren, Miren Zulaica, Eloy Rodríguez Rodríguez, Bernhard Hemmer, Martijn A. Huisman, Thomas Gasser, Peter Heutink, Jason A. Chen, Mercè Boada, Maria Carolina Dalmasso, Xue Wang, Dennis W. Dickson, Florian Then Bergh, Lyduine Collij, Kaj Blennow, Manuel A. Friese, Juan Fortea, Netherlands Brain Bank, and Sonja W. Scholz

Subjects
medicine.medical_specialty, Parkinson's disease, business.industry, Dementia with Lewy bodies, Odds ratio, Disease, medicine.disease, Progressive supranuclear palsy, Internal medicine, Cohort, Medicine, Dementia, business, Frontotemporal dementia
Abstract

Background: PLCG2 plays an important role in immune system signaling, and is expressed in several immune cell types including microglia in the brain. In 2017, the genetic variant rs72824905 (p.Pro522Arg) in the PLCG2 gene (Phospholipase C Gamma 2) was associated with a reduced risk of Alzheimer's disease (AD). Here we investigated whether the rs72824905 variant had a similar protective effect on six other brain diseases. We further tested if rs72824905 increases the likelihood of longevity, since a reduced risk of neurodegenerative diseases might associate with general survival. Methods: We investigated the effect of carrying rs72824905 on disease risk in a total of 53,627 patients with one of seven brain diseases. We studied AD (N = 4,985), frontotemporal dementia (FTD) (N = 2,437), dementia with Lewy-bodies (DLB) (N = 1,446), progressive supranuclear palsy (PSP) (N = 882), Parkinson's disease (PD) (N = 28,448) amyotrophic lateral sclerosis (ALS) (N = 10,953) and multiple sclerosis (MS) (N = 4,476) by comparing them with in total 149,290 controls using logistic regression models. Next, we studied the effect of carrying rs72824905 on longevity by comparing individuals who reached at least 90 years (N = 3,516) with individuals who died before age 90 years or were last screened before 90 years (N = 9,677). In addition, we studied the association of rs72824905 with survival after the age of 90 in a subset of long-lived individuals followed until death. Finally, we supported our findings by studying by-proxy phenotypes in the ~450.000 participants of the UK Biobank. We associated the rs72824905 genotypes of UK Biobank participants with parental history of dementia as proxy for dementia and as a proxy for longevity we studied parental age over 90 as well as parental age over 95 years of age. All individuals were of European ancestry. Results: The rs72824905-G allele associated with a reduced AD risk (Odds ratio (OR) = 0·57, p = 4·7×10-4), a reduced DLB risk (OR = 0·54, p = 4·5×10-2) and reduced FTD risk (OR = 0·61, p = 1·0×10 2). We did not find evidence for association of rs72824905 with the risks of PSP (OR = 1·46, p = 0·19), PD (OR = 1·18, p = 0·10), ALS (OR = 1·07, p = 0·26) or MS (OR = 0·99, p = 0·95). The rs72824905-G allele was associated with a 1·49 increased likelihood of reaching >90 years (p = 6.4×10-3): variant carriers lived longer after the age of 90 years, median 4.7 (inter quartile range = 1·9 - 7·4) years compared to non-carriers 3.3 (IQR = 1·4 - 5·8) (Hazard ratio = 0·75, p = 0·07). By-proxy analyses supported the associations of rs728824905 with dementia as well as longevity. Variant carriers had a lower likelihood of having a parent with dementia (OR = 0·88, p = 1·8×10 3) and had a significantly increased likelihood of having a parent aged >95 years (OR = 1·19, p = 2·1×10-2). Conclusions: Our results show that rs72824905 in PLCG2 protects from AD, DLB and FTD and increases the likelihood of longevity. Together, our findings highlight a central role for PLCG2 related immune signaling in the brain, which should be the subject of future studies as a drug target for multiple brain diseases. Funding Statement: The authors present a short description of 16 cohorts, often including multiple sites or studies, that contributed to this manuscript and their funding sources in Supplementary Table 1: Amsterdam dementia Cohort (ADC), 100-Plus study, German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe), Brain compendium, Clinical AD, Sweden, Danish data, Fundacio ACE (FACE), Genetics of Healthy Ageing Study (GEHA – NL), Gothenburg Birth Cohort (GBC) Studies, International FTD-Genomics Consortium (IFGC), Kompetenznetz Multiple Sklerose (KKNMS), Longitudinal Aging Study Amsterdam (LASA), Leiden Longevity Study, Maria Carolina Dalmasso, Mayo Clinic AD, DLB, PD, PSP, NDRU cohort, Oviedo, Pascual Sanchez-Juan, Project MinE, Risk and modifying factors in Fronto Temporal Dementia (RiMoD-FTD): follows The SPIN cohort, San Sebastian, UK Biobank analysis, IPDGC (The International Parkinson Disease Genomics Consortium). Declaration of Interests: The authors declare no competing interest related to this work. Ethics Approval Statement: Studies were approved by corresponding ethics committees and informed consent was obtained for all participants.

Published
2018

78. Investigating the genetic architecture of dementia with Lewy bodies:a two-stage genome-wide association study

Author

Andrew B. Singleton, David M. A. Mann, Karen Marder, Dena G. Hernandez, Olaf Ansorge, Juan C. Troncoso, Eliezer Masliah, Neill R. Graff-Radford, Claire Troakes, Pentti J. Tienari, Geidy E. Serrano, Monica Diez-Fairen, Peter St George-Hyslop, Safa Al-Sarraj, Tatiana Orme, John Q. Trojanowski, Rita Guerreiro, Andrew J. Lees, Olga Pletnikova, Estrella Morenas-Rodríguez, Kristelle Brown, Valentina Escott-Price, Anne Braae, Michael G. Heckman, Claire E. Shepherd, Janice L. Holton, Suzanne Lesage, Glenda M. Halliday, Jordi Clarimón, Minna Oinas, Isabel Santana, Imelda Barber, Lawrence S. Honig, Ekaterina Rogaeva, Elisabet Londos, Liisa Myllykangas, Ronald C. Petersen, Yaroslau Compta, Douglas Galasko, Stuart Pickering-Brown, Henrik Zetterberg, Vivianna M. Van Deerlin, Celia Kun-Rodrigues, Dennis W. Dickson, Sonja W. Scholz, Tamas Revesz, Kevin Morgan, Lee Darwent, Afina W. Lemstra, Miquel Aguilar, John C. Morris, Brad F. Boeve, Laura Parkkinen, Jose Bras, Tanis J. Ferman, Nigel J. Cairns, David J. Stone, Owen A. Ross, Tammaryn Lashley, Pau Pastor, John D. Eicher, John Hardy, Alberto Lleó, Lorraine N. Clark, Thomas G. Beach, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, haplotype, genotype, Genome-wide association study, Disease, genetic risk, methods [Genome-Wide Association Study], Cohort Studies, 0302 clinical medicine, genetics [Lewy Body Disease], data base, genetic variability, genetics, diffuse Lewy body disease, clinical trial, Parkinson Disease, cohort analysis, 3. Good health, priority journal, Manchester Institute for Collaborative Research on Ageing, Genome-Wide Association Study/methods, Medical genetics, Cohort study, Lewy Body Disease, medicine.medical_specialty, ResearchInstitutes_Networks_Beacons/MICRA, gene locus, phenotype, European, Article, 03 medical and health sciences, autopsy, Internal medicine, medicine, Dementia, Humans, controlled study, human, procedures, ddc:610, genome-wide association study, Lewy body, Dementia with Lewy bodies, business.industry, association, Odds ratio, medicine.disease, major clinical study, Lewy Body Disease/genetics, 030104 developmental biology, multicenter study, Lewy Bodies, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BACKGROUND: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.METHODS: In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage.FINDINGS: This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14-2·70; p=1·05 × 10-48), SNCA (rs7681440; OR 0·73, 0·66-0·81; p=6·39 × 10-10), an GBA (rs35749011; OR 2·55, 1·88-3·46; p=1·78 × 10-9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27-1·79; p=2·32 × 10-6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%.INTERPRETATION: Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.FUNDING: The Alzheimer's Society and the Lewy Body Society.

Published
2018

79. Classification of GBA Variants and Their Effects in Synucleinopathies

Author

Cornelis Blauwendraat, Sonja W. Scholz, Mary B. Makarious, Roy N. Alcalay, and Ziv Gan-Or

Subjects
Lewy Body Disease, Synucleinopathies, Neurology, business.industry, Mutation, alpha-Synuclein, Glucosylceramidase, Humans, Medicine, Neurology (clinical), Computational biology, business
Published
2019

80. Identification of new α-synuclein regulator by nontraditional drug development pipeline

Author

Xi, Chen and Sonja W, Scholz

Subjects
Drug Development, alpha-Synuclein, Humans, Parkinson Disease, Article, Signal Transduction
Abstract

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson’s disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

Published
2017

81. C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Author

Sonja W. Scholz, Olga Pletnikova, Alexander Pantelyat, Barbara J. Crain, Liana S. Rosenthal, Juan C. Troncoso, Joshua T. Geiger, Ted M. Dawson, Marilyn S. Albert, Argye E. Hillis, and Karissa C. Arthur

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, business.industry, Dementia with Lewy bodies, Extramural, medicine.disease, C9orf72 Protein, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, C9orf72, mental disorders, medicine, Neurology (clinical), Amyotrophic lateral sclerosis, Repeat analysis, Neurodegenerative dementia, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. Objective: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. Methods: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. Results: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. Conclusion: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

Published
2016

82. Multiple system atrophy as emerging template for accelerated drug discovery in α-synucleinopathies

Author

Gregor K. Wenning, Nadia Stefanova, Kurt A. Jellinger, Sonja W. Scholz, Klaus Seppi, Angelo Antonini, Florian Krismer, and Werner Poewe

Subjects
Parkinson's disease, Synucleinopathies, Central nervous system, Clinical Neurology, Drug development, Disease, Atrophy, Drug Discovery, medicine, Humans, Point of View, business.industry, Drug discovery, Parkinson Disease, Multiple system atrophy, medicine.disease, nervous system diseases, Clinical trial, medicine.anatomical_structure, Neurology, alpha-Synuclein, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience
Abstract

There is evidence that the α-synucleinopathies Parkinson's disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Despite the considerable clinical overlap in the early disease stages, MSA-P, in contrast to PD, is fatal and rapidly progressive. Moreover recent clinical studies have shown that surrogate markers of disease progression can be quantified easily and may reliably depict the rapid course of MSA. We therefore posit that, MSA-P may be exploited as a filter barrier in the development of disease-modifying therapeutic strategies targeting common pathophysiological mechanisms of α-synucleinopathies. This approach might reduce the number of negative phase III clinical trials, and, in turn, shift the available resources to earlier development stages, thereby increasing the number of candidate compounds validated., Highlights • α-synucleinopathies overlap at multiple levels. • α-synucleinopathies are characterized by an abnormal deposition of α-synuclein. • Validated surrogate markers in MSA reliably monitor disease progression. • MSA may serve as a template disease for other α-synucleinopathies.

Published
2014
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83. Genetic analysis of neurodegenerative diseases in a pathology cohort

Author

Cornelis Blauwendraat, Olga Pletnikova, Joshua T. Geiger, Natalie A. Murphy, Yevgeniya Abramzon, Gay Rudow, Adamantios Mamais, Marya S. Sabir, Barbara Crain, Sarah Ahmed, Liana S. Rosenthal, Catherine C. Bakker, Faraz Faghri, Ruth Chia, Jinhui Ding, Ted M. Dawson, Alexander Pantelyat, Marilyn S. Albert, Mike A. Nalls, Susan M. Resnick, Luigi Ferrucci, Mark R. Cookson, Argye E. Hillis, Juan C. Troncoso, and Sonja W. Scholz

Subjects
Male, 0301 basic medicine, Aging, Genotyping Techniques, Disease, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Genetic analysis, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, C9orf72, PSEN1, medicine, Humans, Genotyping, Genetic Association Studies, Aged, Aged, 80 and over, Genetics, DNA Repeat Expansion, C9orf72 Protein, General Neuroscience, Neurodegeneration, Neurodegenerative Diseases, Middle Aged, medicine.disease, LRRK2, High-Throughput Screening Assays, 030104 developmental biology, Molecular Diagnostic Techniques, Mutation, Cohort, Female, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

Published
2019

85. Restless legs syndrome: is it all in the genes?

Author

Sonja W. Scholz

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, business.industry, medicine, MEDLINE, Neurology (clinical), Restless legs syndrome, medicine.disease, business, Bioinformatics, Gene
Published
2017

86. C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Author

Joshua T, Geiger, Karissa C, Arthur, Ted M, Dawson, Liana S, Rosenthal, Alexander, Pantelyat, Marilyn, Albert, Argye E, Hillis, Barbara, Crain, Olga, Pletnikova, Juan C, Troncoso, and Sonja W, Scholz

Subjects
Aged, 80 and over, Lewy Body Disease, Male, DNA Repeat Expansion, C9orf72 Protein, Mutation, Humans, Proteins, Female, White People, Article, Aged
Abstract

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion.To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients.We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay.No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB.Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

Published
2016

87. Contents Vol. 16, 2016

Author

Marilyn S. Albert, Kah-Leong Lim, Genny Orso, Eniko Veronika Kovari, Alessandro Padovani, Sonja W. Scholz, Chiara Mattei, José Berciano, François Herrmann, Davide Massucco, Matteo Pardini, Hans Wilhelm Müller, Markus Beu, Shyuan T. Ngo, Karissa C. Arthur, Jasper Verbree, Joshua T. Geiger, Zeeshan Mushtaq, Bing-Han Chai, Stefano Ferrea, Chee-Hoe Ng, Juan C. Troncoso, Jian-xiu Zhu, Carlo Scialò, José Manuel López-Vega, Olga Pletnikova, Panteleimon Giannakopoulos, Federica Rossi, Francesca Benassi, Zhi-jian Su, Caroline G.L. Lee, Druckerei Stückle, Samuel S. Chong, Peng Lei, Constantin Bouras, Richard G. Wise, Pamela A. McCombe, Saumitra Dey Choudhury, Jacqueline A.M. Wubben, Eduards Mamlins, Qi-hao Zhang, Silvia Compostella, William L. Klein, Leonardo Emberti Gialloreti, Peng-hui Yang, Mingjue Zhao, Ana Santurtún, Pascual Sánchez-Juan, Henry Basil Adeline, Liana S. Rosenthal, Ingrid H.C.H.M. Philippens, Davide Sassos, Matthis Synofzik, Vimlesh Kumar, August B. Smit, Maura Brunetti, Lars Wojtecki, Sven Hammesfahr, Xian-ying Zhang, Ezio Giacobini, Lars Dinkelbach, Jordan Grafman, Christina Antke, Barbara Borroni, Javier Riancho, Jochen Klenk, Alexia-Sabine Moldovan, Frank Krueger, Armand Savioz, Robert D. Henderson, Cheng-Wu Zhang, Clemens Becker, Barbara J. Crain, Ashley I. Bush, Ilaria Callegari, Zara A. Ioannides, Pablo Lozano-Cuesta, Massimiliano Filosto, Ronald E. van Kesteren, Mario Amore, Adriano Chiò, Sigrid K. Franke, Craig Blackstone, Alfons Schnitzler, Sri Krishna Gangwar, Matthias J.P. van Osch, Alexander Pantelyat, J M Polo, Flavio Nobili, Fabrizio Rinaldi, Hai-Yang Law, Ya-dong Huang, Özgür Yaldizli, Qi Xiang, Frederik J. Steyn, Andrea Pilotto, Carlo Serrati, Cornelia Schatton, Sam Hofman, Massimo Filippi, Matthew J. Fraidakis, Satz Mengensatzproduktion, Esther A. H. Warnert, Karin Srulijes, Argye E. Hillis, Lars Schwickert, Martin Südmeyer, Walter Maetzler, Eugenia T.E. Hong, Ted M. Dawson, Leonardo Cocito, and Maura Cosseddu

Subjects
Neurology, Neurology (clinical)
Published
2016

88. Genome-wide estimate of the heritability of Multiple System Atrophy

Author

Dena G. Hernandez, A Sailer, AB Singleton, Timothy Ryan Price, Mike A. Nalls, Henry Houlden, Aude Nicolas, Monica Federoff, and Sonja W. Scholz

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Linkage disequilibrium, Ataxia, Genotype, Genome-wide association study, Disease, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Progressive supranuclear palsy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Atrophy, stomatognathic system, parasitic diseases, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Genetics, business.industry, Parkinsonism, Parkinson Disease, Multiple System Atrophy, medicine.disease, nervous system diseases, 030104 developmental biology, nervous system, Neurology, Case-Control Studies, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis.We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform.We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis.MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants.

Published
2015

89. ADORA1mutations are not a common cause of Parkinson's disease and dementia with Lewy bodies

Author

Cornelis Blauwendraat, Dena G. Hernandez, Mike A. Nalls, Juan C. Troncoso, J. Raphael Gibbs, Monica Federoff, Javier Simón-Sánchez, Christopher Letson, Sonja W. Scholz, Joshua T. Geiger, Jinhui Ding, and Olga Pletnikova

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Parkinson's disease, business.industry, Dementia with Lewy bodies, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2016

90. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study

Author

Lilja Jansson, Terhi Peuralinna, Shaoi-Lin Lai, Pentti J. Tienari, Dena G. Hernandez, David Heckerman, Sonja W. Scholz, Hannu Laaksovirta, Liisa Myllykangas, J. Raphael Gibbs, Raimo Sulkava, Bryan J. Traynor, Mike A. Nalls, and Jennifer C. Schymick

Subjects
Genetics, 0303 health sciences, education.field_of_study, Linkage disequilibrium, business.industry, Population, Haplotype, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Odds ratio, medicine.disease, Article, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Neurology (clinical), Amyotrophic lateral sclerosis, education, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Summary Background The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population. Methods We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus. Findings We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318 167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10 −8 ), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10 −11 ) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10 −33 when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2–39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7–48·1) and that for D90A homozygosity was 25·5% (16·9–34·1). Interpretation The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. Funding National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.

Published
2010

91. Identification of new α-synuclein regulator by nontraditional drug development pipeline

Author

Sonja W. Scholz and Xi Chen

Subjects
0301 basic medicine, Alpha-synuclein, Pipeline (computing), Regulator, Computational biology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Neurology, chemistry, Drug development, Identification (biology), α synuclein, Neurology (clinical), Signal transduction, 030217 neurology & neurosurgery
Published
2018

92. Genome-wide association study reveals genetic risk underlying Parkinson's disease

Author

Olaf Riess, Michael S. Okun, John Hardy, Henry Houlden, Peter Lichtner, Ryan R. Zonozi, Christian Gieger, Albert R. Hollenbeck, Stefan Schreiber, Coro Paisán-Ruiz, Jose Bras, Günther Deuschl, Monica Federoff, Sonja W. Scholz, Michael Bonin, Daniela Berg, Javier Simón-Sánchez, Bryan J. Traynor, Thomas Illig, Christine Klein, Mike A. Nalls, Claudia Schulte, Arthur Schatzkin, Alison Goate, Rejko Krüger, Jianjun Gao, Kelly D. Foote, Sampath Arepalli, Grisel Lopez, J. Raphael Gibbs, Nicholas W. Wood, Manu Sharma, Hubert H. Fernandez, Delia Lorenz, Marcel P. van der Brug, Michael Steffens, Joel S. Perlmutter, Mark R. Cookson, Yikyung Park, Thomas Gasser, Andrew B. Singleton, Katrina Gwinn, Xuemei Huang, Dena G. Hernandez, Stephen J. Chanock, Honglei Chen, Brad A. Racette, Human genetics, and NCA - Neurodegeneration

Subjects
Linkage disequilibrium, Locus (genetics), Genome-wide association study, Biology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Japan, genetics [Parkinson Disease], Risk Factors, ddc:570, Genetic variation, Genetics, Humans, Genetic Predisposition to Disease, Allele frequency, 030304 developmental biology, 0303 health sciences, Genetic heterogeneity, Haplotype, Genetic Variation, Parkinson Disease, LRRK2, epidemiology [Parkinson Disease], 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Published
2009

93. Susceptibility genes in movement disorders

Author

Andrew B. Singleton and Sonja W. Scholz

Subjects
Neurogenomics, Genetics, Candidate gene, Movement disorders, Positional cloning, Genome-wide association study, Disease, Computational biology, Biology, Neurology, Genetic variation, medicine, Neurology (clinical), medicine.symptom, Genetic association
Abstract

During the last years, remarkable progress in our understanding of molecular genetic mechanisms underlying movement disorders has been achieved. The successes of linkage studies, followed by positional cloning, have dominated the last decade and several genes underlying monogenic disorders have been discovered. The pathobiological understanding garnered from these mutations has laid the foundation for much of the search for genetic loci that confer risk for, rather than cause, disease. With the introduction of whole genome association studies as a novel tool to investigate genetic variation underlying common, complex diseases, a new era in neurogenomics has just begun. As the field rapidly moves forward several new challenges and critical questions in clinical care have to be addressed. In this review, we summarize recent advances in the discovery of susceptibility loci underlying major movement disorders, explain the newest methodologies and tools employed for finding and characterizing genes and discuss how insights into the molecular genetic basis of neurological disorders will impact therapeutic concepts in patient care. © 2008 Movement Disorder Society

Published
2008

94. Structural genomic variation in ischemic stroke

Author

Stephen S. Rich, Robert D. Brown, Mar Matarin, Javier Simón-Sánchez, Andrew B. Singleton, Angela Britton, Cynthia Crews, Scott Silliman, John Hardy, Dena G. Hernandez, Thomas G. Brott, Sonja W. Scholz, Bradford B. Worrall, J. Raphael Gibbs, Hon Chung Fung, Fabienne Wavrant-De Vrièze, James F. Meschia, and L. Douglas Case

Subjects
Male, medicine.medical_specialty, endocrine system diseases, Genomic Structural Variation, Gene Dosage, Genomics, Biology, Polymorphism, Single Nucleotide, White People, Article, Brain Ischemia, Cohort Studies, Cellular and Molecular Neuroscience, Risk Factors, Molecular genetics, mental disorders, Genetics, medicine, Humans, SNP, Copy-number variation, Genetics (clinical), Aged, Genetic association, Aged, 80 and over, Genome, Human, Middle Aged, Human genetics, Stroke, Case-Control Studies, North America, Female, Human genome
Abstract

Technological advances in molecular genetics allow rapid and sensitive identification of genomic copy number variants (CNVs). This, in turn, has sparked interest in the function such variation may play in disease. While a role for copy number mutations as a cause of Mendelian disorders is well established, it is unclear whether CNVs may affect risk for common complex disorders. We sought to investigate whether CNVs may modulate risk for ischemic stroke (IS) and to provide a catalog of CNVs in patients with this disorder by analyzing copy number metrics produced as a part of our previous genome-wide single-nucleotide polymorphism (SNP)-based association study of ischemic stroke in a North American white population. We examined CNVs in 263 patients with ischemic stroke (IS). Each identified CNV was compared with changes identified in 275 neurologically normal controls. Our analysis identified 247 CNVs, corresponding to 187 insertions (76%; 135 heterozygous; 25 homozygous duplications or triplications; 2 heterosomic) and 60 deletions (24%; 40 heterozygous deletions; 3 homozygous deletions; 14 heterosomic deletions). Most alterations (81%) were the same as, or overlapped with, previously reported CNVs. We report here the first genome-wide analysis of CNVs in IS patients. In summary, our study did not detect any common genomic structural variation unequivocally linked to IS, although we cannot exclude that smaller CNVs or CNVs in genomic regions poorly covered by this methodology may confer risk for IS. The application of genome-wide SNP arrays now facilitates the evaluation of structural changes through the entire genome as part of a genome-wide genetic association study.

Published
2008

95. Genomewide SNP assay reveals mutations underlying Parkinson disease

Author

J. Raphael Gibbs, Javier Simón-Sánchez, Andrew B. Singleton, John Hardy, Sonja W. Scholz, Dena G. Hernandez, H.C. Fung, Maria del Mar Matarin, and Angela Britton

Subjects
Male, Heterozygote, Gene Dosage, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Gene dosage, Gene Duplication, Gene duplication, Genotype, Genetics, Humans, SNP, Genotyping, Genetics (clinical), Aged, Genetic association, Aged, 80 and over, Genome, Human, Reverse Transcriptase Polymerase Chain Reaction, Parkinson Disease, Exons, Middle Aged, Human genetics, Mutation, Female, Gene Deletion
Abstract

Technologies that allow genotyping of more than 100,000 polymorphisms in a single assay enable the execution of genomewide SNP (GWSNP) association studies to identify common genetic variants underlying traits. Less appreciated is the ability of GWSNP assays to map and directly identify rare mutations that cause disease. Here we show the use of this approach in identifying rare structural mutations involved in disease using a large cohort of Parkinson disease (PD) patients and neurologically normal controls by examination of genotype data and copy number metrics. This approach revealed a patient with homozygous mutation at the PARK2 locus. In addition, two heterozygous deletion mutations and five heterozygous duplication mutations within PARK2 were identified in PD subjects and controls. All mutations were confirmed by independent gene dosage experiments. These data demonstrate the utility of this approach in the direct detection of mutations that underlie disease.

Published
2008

96. Genotype, haplotype and copy-number variation in worldwide human populations

Author

Angela Britton, Hon Chung Fung, Javier Simón-Sánchez, Jenna M. VanLiere, Kai Wang, Andrew B. Singleton, Sonja W. Scholz, Maja Bucan, Zachary A. Szpiech, J. Raphael Gibbs, John Hardy, Joyce van de Leemput, Bryan J. Traynor, Jose Bras, Howard M. Cann, Rita Guerreiro, Noah A. Rosenberg, Mar Matarin, Jennifer C. Schymick, Mattias Jakobsson, Dena G. Hernandez, Paul Scheet, Ian Rafferty, and James H. Degnan

Subjects
Genetics, Linkage disequilibrium, education.field_of_study, Multidisciplinary, Geography, Genome, Human, Population, Haplotype, Gene Dosage, Genetic Variation, Population genetics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Genetics, Population, Haplotypes, Chromosomes, Human, Pair 2, Africa, Humans, SNP, Copy-number variation, education, Alleles, Founder effect
Abstract

Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.

Published
2008

97. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data

Author

Adriano Chiò, Jeffrey D. Rothstein, John Hardy, Cynthia Crews, Gabriella Restagno, Federica Lombardo, Dalia Kasperaviciute, Hon Chung Fung, Jennifer C. Schymick, Gabriele Mora, Sonja W. Scholz, Andrew B. Singleton, Sampath Arepalli, J. Raphael Gibbs, Bryan J. Traynor, Lucie Bruijn, Dena G. Hernandez, Mar Matarin, and Angela Britton

Subjects
Adult, Genetic Markers, Male, casi sporadici, Linkage disequilibrium, Genotype, DNA Mutational Analysis, Population, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Reference Values, Databases, Genetic, medicine, Humans, Sclerosi laterale amiotrofica, genetica, Genetic Predisposition to Disease, Genetic Testing, Amyotrophic lateral sclerosis, education, Molecular Biology, Genotyping, Aged, Genetic testing, Aged, 80 and over, Genetics, Genomic Library, education.field_of_study, Public Sector, medicine.diagnostic_test, Amyotrophic Lateral Sclerosis, Middle Aged, medicine.disease, SNP genotyping, Mutation, Female, Neurology (clinical)
Abstract

Summary Background The cause of sporadic ALS is currently unknown. Despite evidence for a role for genetics, no common genetic variants have been unequivocally linked to sporadic ALS. We sought to identify genetic variants associated with an increased or decreased risk for developing ALS in a cohort of American sporadic cases. Methods We undertook a genome-wide association study using publicly available samples from 276 patients with sporadic ALS and 271 neurologically normal controls. 555 352 unique SNPs were assayed in each sample using the Illumina Infinium II HumanHap550 SNP chip. Findings More than 300 million genotypes were produced in 547 participants. These raw genotype data are freely available on the internet and represent the first publicly accessible SNP data for ALS cases. 34 SNPs with a p value less than 0·0001 (two degrees of freedom) were found, although none of these reached significance after Bonferroni correction. Interpretation We generated publicly available genotype data for sporadic ALS patients and controls. No single locus was definitively associated with increased risk of developing disease, although potentially associated candidate SNPs were identified.

Published
2007

98. GBA mutations and Parkinson disease: when genotype meets phenotype

Author

Sonja W. Scholz and Beom S. Jeon

Subjects
Genetics, Male, Parkinson Disease, Disease, Biology, Phenotype, Severity of Illness Index, Article, Pathogenesis, Jews, Genotype, Mutation, Glucosylceramidase, Humans, Female, Neurology (clinical), Genetic risk, Gene, Glucocerebrosidase
Abstract

The last 2 decades have seen remarkable advances in our understanding of genetic risk factors underlying the pathogenesis of Parkinson disease (PD). One of the most surprising discoveries was that mutations in GBA (glucosidase, beta, acid), coding for the lysosomal enzyme glucocerebrosidase, have a substantial role in PD. While homozygous GBA mutations were known for some time as the cause of Gaucher disease, subsequent clinical, neuropathologic, and genetic studies established that heterozygous and occasional homozygous mutations in this gene are also common risk factors for PD, particularly in the Ashkenazi-Jewish population.1–7

Published
2015

99. A genome-wide association study of myasthenia gravis

Author

Sampath Arepalli, Gabriella Restagno, David P. Richman, Julaine Florence, Michael Benatar, Sean Chong, Miriam Freimer, Henry J. Kaminski, Sonja W. Scholz, Robert M. Pascuzzi, Andrea M. Corse, Carlo Provenzano, Bryan J. Traynor, Emanuela Bartoccioni, Janel O. Johnson, Srikanth Muppidi, Daniel B. Drachman, Gil I. Wolfe, Mike A. Nalls, Janice M. Massey, Adriano Chiò, Manisha Chopra, Derrick Blackmore, Flavia Scuderi, Mamatha Pasnoor, Roberta Ricciardi, Joel Oger, J. Raphael Gibbs, April McVey, Edoardo Errichiello, Charlie Wulf, Theresa Jiwa, Mazen M. Dimachkie, Hannah A. Pliner, Richard J. Barohn, Michael W. Nicolle, Zaeem A. Siddiqi, Giuseppe Marangi, Amelia Evoli, Vinay Chaudhry, James F. Howard, Wilma J. Koopman, Bernadette Lipscomb, Mark Macek, Michelangelo Maestri, Dena G. Hernandez, Alan Pestronk, Julie Rowin, John T. Kissel, Donald B. Sanders, Mario Sabatelli, Michelle M. Mezei, Alan E. Renton, Yevgeniya Abramzon, and Aimee Soloway

Subjects
Male, Genome-wide association study, Settore MED/03 - GENETICA MEDICA, Settore MED/05 - PATOLOGIA CLINICA, Gene Frequency, 2.1 Biological and endogenous factors, GWAS, CTLA-4 Antigen, Aetiology, Age of Onset, Single Nucleotide, Middle Aged, Cohort, Cognitive Sciences, Female, medicine.symptom, Adult, Weakness, medicine.medical_specialty, Neuromuscular disease, Genotype, Clinical Sciences, Miastenia gravis, Single-nucleotide polymorphism, Autoimmune Disease, Polymorphism, Single Nucleotide, HLA-DQ alpha-Chains, Rare Diseases, Arts and Humanities (miscellaneous), Clinical Research, Internal medicine, Myasthenia Gravis, medicine, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Neurology & Neurosurgery, business.industry, Human Genome, Case-control study, Neurosciences, Odds ratio, medicine.disease, Myasthenia gravis, United States, Case-Control Studies, Immunology, Genome-Wide Association Study, Neurology (clinical), business
Abstract

Importance Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. Objective To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. Design, Setting, and Participants DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. Main Outcomes and Measures We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10 −8 was set for genome-wide significance after Bonferroni correction for multiple testing. Results In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10 −8 ; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10 −8 ; odds ratio, 2.31; 95% CI, 2.02 - 2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10 −9 ; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10 −12 ; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 ( HLA-DQA1 ; rs9271871; P = 7.02 × 10 −18 ; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases ( HLA-DQA1 ; rs601006; P = 2.52 × 10 −11 ; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. Conclusions and Relevance Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Published
2015

100. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data

Author

Kelly D. Foote, J. Raphael Gibbs, John Hardy, Jennifer C. Schymick, Carl D. Langefeld, Angela Britton, Fabienne Wavrant-De Vrièze, Sonja W. Scholz, Mar Matarin, Matt L Stiegert, Elizabeth Peckham, Michael S. Okun, Hubert H. Fernandez, Ronald J. Mandel, Ramon L. Rodriguez, Javier Simón-Sánchez, H.C. Fung, Dena G. Hernandez, Katrina Gwinn-Hardy, and Andrew B. Singleton

Subjects
Male, Parkinson's disease, Genotype, Single-nucleotide polymorphism, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Cohort Studies, Gene Frequency, Databases, Genetic, medicine, Humans, SNP, Genetic variability, International HapMap Project, Genotyping, Aged, Aged, 80 and over, Genetics, Chromosome Mapping, Parkinson Disease, Genomics, Middle Aged, medicine.disease, Female, Neurology (clinical)
Abstract

Summary Background Several genes underlying rare monogenic forms of Parkinson's disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinson's disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinson's disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. Methods We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinson's disease patients (n=267) and neurologically normal controls (n=270). More than 408 000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. Findings We have produced around 220 million genotypes in 537 participants. This raw genotype data has been publicly posted and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. Interpretation We generated publicly available genotype data for Parkinson's disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.

Published
2006

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