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16 results on '"Frank P. Diekstra"'

1. 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
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2. Whole blood transcriptome analysis in amyotrophic lateral sclerosis: A biomarker study

Author

Wouter van Rheenen, Oliver Harschnitz, Michael A. van Es, Ewout J N Groen, Jan H. Veldink, Frank P. Diekstra, Henk Jan Westeneng, Christiaan G J Saris, Leonard H. van den Berg, Paul W.J. van Vught, Hylke M. Blauw, and Kristel R. van Eijk

Subjects
0301 basic medicine, Male, Support Vector Machine, Physiology, lcsh:Medicine, Gene Expression, Protein domains, Biochemistry, Transcriptome, Cohort Studies, Motor Neuron Diseases, 0302 clinical medicine, Gene expression, Medicine and Health Sciences, Amyotrophic lateral sclerosis, lcsh:Science, Whole blood, Multidisciplinary, Agricultural and Biological Sciences(all), DEAD-box, Neurodegenerative Diseases, Genomics, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Prognosis, Healthy Volunteers, Body Fluids, Nucleic acids, Blood, Neurology, Biomarker (medicine), Female, Anatomy, Transcriptome Analysis, Signal Transduction, Research Article, Computational biology, Biology, Biological pathway, Diagnosis, Differential, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, medicine, Journal Article, Genetics, Humans, Survival analysis, Aged, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, lcsh:R, Amyotrophic Lateral Sclerosis, Case-control study, Biology and Life Sciences, Proteins, Computational Biology, medicine.disease, Genome Analysis, Survival Analysis, 030104 developmental biology, RNA processing, Case-Control Studies, Feasibility Studies, RNA, lcsh:Q, RNA transport, 030217 neurology & neurosurgery, Biomarkers, Genetics and Molecular Biology(all)
Abstract

The biological pathways involved in amyotrophic lateral sclerosis (ALS) remain elusive and diagnostic decision-making can be challenging. Gene expression studies are valuable in overcoming such challenges since they can shed light on differentially regulated pathways and may ultimately identify valuable biomarkers. This two-stage transcriptome-wide study, including 397 ALS patients and 645 control subjects, identified 2,943 differentially expressed transcripts predominantly involved in RNA binding and intracellular transport. When batch effects between the two stages were overcome, three different models (support vector machines, nearest shrunken centroids, and LASSO) discriminated ALS patients from control subjects in the validation stage with high accuracy. The models’ accuracy reduced considerably when discriminating ALS from diseases that mimic ALS clinically (N = 75), nor could it predict survival. We here show that whole blood transcriptome profiles are able to reveal biological processes involved in ALS. Also, this study shows that using these profiles to differentiate between ALS and mimic syndromes will be challenging, even when taking batch effects in transcriptome data into account.

Published
2018

3. The role of de novo mutations in the development of amyotrophic lateral sclerosis

Author

Nicola Ticozzi, Peter M. Andersen, Albert C. Ludolph, Antonia Ratti, Nicolai Marroquin, Jan H. Veldink, Frank P. Diekstra, John Landers, Federico Verde, Raymond D. Schellevis, Kevin P. Kenna, Vincenzo Silani, Barbara Castellotti, Bernard Muller, Cinzia Gellera, Viviana Pensato, Cinzia Tiloca, Peter Nürnberg, Christian Kubisch, Sara L. Pulit, Laurent C. Francioli, Perry T.C. van Doormaal, Janine Altmüller, Susanne Motameny, Joachim Wolf, Daniel J. Overste, Jochen H. Weishaupt, Leonard H. van den Berg, Annelot M. Dekker, Alexander E Volk, and Daniela Calini

Subjects
0301 basic medicine, Male, Mutation rate, medicine.medical_specialty, Population, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Mutation Rate, Databases, Genetic, Protein Interaction Mapping, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Protein Interaction Maps, Amyotrophic lateral sclerosis, education, Genetics (clinical), Exome sequencing, Alleles, Genetic Association Studies, education.field_of_study, Mutation, C9orf72 Protein, Whole Genome Sequencing, Amyotrophic Lateral Sclerosis, medicine.disease, 030104 developmental biology, Disease Pathway, Amino Acid Substitution, Case-Control Studies, Medical genetics, Female, 030217 neurology & neurosurgery
Abstract

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10(−15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

Published
2017

4. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author

Cristina Cereda, Jurjen J. Luykx, Sandra Meier, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, John Landers, Silvana Penco, Marian L. Hamshere, Frank Dudbridge, Mari Nelis, Dick Schijven, Jimmy Lee, Sarah E. Bergen, Alessandro Padovani, Nicholas W. Wood, Meraida Polak, Hannelore Ehrenreich, Nancy G. Buccola, Noa Carrera, Stefan Herms, Panos Roussos, Marion Friedl, Teimuraz Silagadze, Jim van Os, Annette M. Hartmann, Ole A. Andreassen, R. Jeroen Pasterkamp, Sibylle G. Schwab, Aleksey Shatunov, Eli A. Stahl, David A. Collier, Farooq Amin, Michael Conlon O'Donovan, Guiqing Cai, Kung-Yee Liang, Denis C. Bauer, Charles Curtis, Brion S. Maher, Ashley R. Jones, Sara L. Pulit, Sarah Tosato, Milan Macek, Vivianna M. Van Deerlin, Vincenzo Silani, Pietro Fratta, Bettina Konte, Rosanna Tortelli, Dan Rujescu, T. Scott Stroup, Elizabeth Bevilacqua, Christian Lunetta, Bradley T. Webb, Christophe Tzourio, Patrick Vourc'h, Joel N. Hirschhorn, Gilbert Bensimon, Timothy G. Dinan, Thomas G. Schulze, Richard A. Belliveau, Daniel R. Weinberger, Andrew McQuillin, Qingqin S. Li, Orla Hardiman, Claudine Laurent, Masashi Ikeda, Tim Kahlke, Rodney J. Scott, Frans Henskens, Tune H. Pers, Wolfgang Lieb, Christian Hammer, Elvira Bramon, Hana Kuzelova-Ptackova, Raquelle I. Mesholam-Gately, Ingrid Melle, Nadine Cohen, David Cohen, Nazli Basak, Elisabeth Stögmann, Nelson B. Freimer, Peter Eichhammer, J. Mallet, Preben Bo Mortensen, Robert H. Brown, Wouter van Rheenen, Roberto Del Bo, Dai Wang, Laurent Essioux, Larry J. Seidman, Hreinn Stefansson, Erik G. Jönsson, Mads V. Hollegaard, Raymond C.K. Chan, Susana Pinto, Alexander Richards, Jubao Duan, Peter Holmans, George Kirov, Pablo V. Gejman, Philippe Amouyel, Stephanie Godard, Dieter B. Wildenauer, Martina Wiedau-Pazos, Stacy Steinberg, Ole Mors, Andres Metspalu, Rolf Adolfsson, Shaun Purcell, Hugh Gurling, Joseph I. Friedman, Erik Söderman, Mark Weiser, Giacomo P. Comi, James A. Knowles, Peter M. Andersen, Brien P. Riley, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Digby Quested, Srinivas Thirumalai, Ulrich Schall, Jan Lubinski, Dragan M. Svrakic, Aaron R. Wolen, S. Hong Lee, Andrew Pocklington, Bernard Lerer, Vahram Haroutunian, Matthew C. Kiernan, Kenneth L. Davis, Assen Jablensky, William Byerley, Karol Estrada, Aarno Palotie, Cinzia Tiloca, Eadbhard O'Callaghan, Perry T.C. van Doormaal, Colm McDonald, Federico Casale, Thomas Meitinger, Robert Freedman, Gerome Breen, Milena Blagojevic-Radivojkov, Ian P. Blair, Ann E. Pulver, Jan H. Veldink, Giancarlo Logroscino, Miaoxin Li, Abraham Reichenberg, Esben Agerbo, Siddharthan Chandran, Patrik K. E. Magnusson, Andrew M. McIntosh, Gianni Sorarù, Maura Brunetti, Xuebin Zheng, Madeline Alexander, James L. Kennedy, Douglas Blackwood, Menachem Fromer, Martilias S. Farrell, Alan R. Sanders, Dominic B. Rowe, Alexis Brice, Jonathan Pimm, Emily H. M. Wong, Jana Strohmaier, André G. Uitterlinden, Andrea Calvo, Carsten Drepper, John Q. Trojanowski, Marcella Rietschel, Siow Ann Chong, Karen E. Morrison, Sang-Yun Oh, Laura Nisenbaum, Margaret O'Brien, Alkes L. Price, Carin J. Meijer, Michael Davidson, John Powell, Petr Slominsky, Wiepke Cahn, Cinzia Gellera, Vihra Milanova, Peter M. Visscher, Patricia T. Michie, Dimitris Dikeos, Jianxin Shi, Veikko Salomaa, Philip Van Damme, James J. Crowley, Younes Mokrab, Valentina Escott-Price, Jesus S. Mora, Stanley V. Catts, David St Clair, Bernhard Landwehrmeyer, John Hardy, Kristin K. Nicodemus, Dominique Campion, Juha Veijola, Wim Robberecht, Thomas Meyer, Peter Lichtner, Christos Pantelis, Markus Weber, Nilo Riva, Jin P. Szatkiewicz, Michele T. Pato, Cinzia Bertolin, Frank P. Diekstra, Simon Arcuti, Bryan J. Mowry, Hon-Cheong So, Adriano Chiò, Viviana Pensato, Yunjung Kim, Jean-François Dartigues, Zita Ausrele Kucinskiene, Inez Myin-Germeys, Jaana Suvisaari, Sophie E. Legge, Roel A. Ophoff, Philippe Corcia, Gerald Nestadt, Stephan Ripke, Kuang Lin, Paola Giusti-Rodríguez, Michael John Owen, Chris C. A. Spencer, Safa Saker-Delye, Robert W. McCarley, Kimberley D. Chambert, Brandon Wormley, Isabella Fogh, Mamede de Carvalho, Pamela J. Shaw, Tõnu Esko, Ronald Y. L. Chan, Jianjun Liu, Tim B. Bigdeli, Christian R. Andres, David M. Hougaard, Michael Gill, Ammar Al-Chalabi, Colm O'Dushlaine, Rick A.A. van der Spek, Gary Donohoe, Tao Li, Jonathan D. Glass, Christopher Shaw, Draga Toncheva, Leonard H. van den Berg, Liene Nikitina-Zake, Morten Mattingsdal, François Salachas, Andrey Khrunin, Line Olsen, Jochen H. Weishaupt, Jo Knight, Katie Sidle, Filip Eftimov, Massimiliano Filosto, Russell L. McLaughlin, Pak C. Sham, Joshua L. Roffman, Thomas Hansen, Naser Durmishi, Deborah A. Nertney, Juha Karjalainen, Robert Swingler, Ditte Demontis, Vaidutis Kučinskas, Jennifer L. Moran, Leo McCluskey, Donald W. Black, Eric F.C. Cheung, Qiang Wang, Olli Pietilainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Annelie Nordin, Wolfgang Maier, Bradley N. Smith, Ettore Beghi, Rosa Capozzo, Garth A. Nicholson, Markus M. Nöuthen, Jordan W. Smoller, Eric Y.H. Chen, Joseph D. Buxbaum, Letizia Mazzini, Andrea Malaspina, Antonio Julià, Stephanie Williams, Tracey L. Petryshen, Christine Payan, Johan G. Eriksson, Carmel M. Loughland, Elodie Drapeau, Lieuwe de Haan, Martin Begemann, Lukas Tittmann, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Jacqueline I. Goldstein, Annelot M. Dekker, Sergi Papiol, Svetlana A. Limborska, René S. Kahn, Shuna Colville, Kelly L. Williams, Pamela Sklar, Diana O. Perkins, Lili Milani, Ayman H. Fanous, Nicola Ticozzi, Fernando Rivadeneira, Marianne de Visser, P. Nigel Leigh, James T.R. Walters, Josef Frank, Aiden Corvin, Silviu Alin Bacanu, John L. Waddington, Stephanie H. Witt, Tiina Paunio, Margot Albus, Catherine Lomen-Hoerth, Sara Marsal, Per Hoffmann, David Curtis, Cindy Maurel, Todd Lencz, Orietta Pansarasa, Manuel Mattheisen, Anneke J. van der Kooi, A. Hofman, Dermot Walsh, Hailiang Huang, Ann Olincy, Anders D. Børglum, Ricardo Rojas-García, William Sproviero, Albert C. Ludolph, Edward M. Scolnick, Danielle Posthuma, George N. Papadimitriou, Michael A. van Es, Fritz Zimprich, F. Anthony O'Neill, Lude Franke, Jouko Lönnqvist, Daniel G. Bradley, Sven Cichon, Susanna Abdulla, Kristel R. van Eijk, Ingrid Agartz, Elisabetta Pupillo, Milica Pejovic-Milovancevic, Antonia Ratti, Henrik B. Rasmussen, Kari Stefansson, Brendan Bulik-Sullivan, Béla Melegh, Stéphanie Millecamps, Janis Klovins, Enrico Domenici, Michael Sendtner, Kai-How Farh, Randy L. Buckner, Albert Hofman, Benjamin M. Neale, Naomi R. Wray, An Goris, Kang Sim, Lauren Elman, Giulio Genovese, Jens R. Wendland, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Sandra D'Alfonso, Cristina Moglia, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Richard W. Orrell, Richard Bruggeman, Kenneth S. Kendler, Alan M. Pittman, Robin M. Murray, Richard E. Straub, Cathryn M. Lewis, Srdjan Djurovic, Vincent Meininger, Jeffrey A. Lieberman, Bertram Müller-Myhsok, Phil Lee, David J. Kavanagh, Srihari Gopal, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Alexandra Durr, Roger Pamphlett, Douglas F. Levinson, Luba Kalaydjieva, Chiara Zecca, Anil K. Malhotra, Andre Franke, Vaughan J. Carr, Steven A. McCarroll, C. Robert Cloninger, Judit Bene, Ina Giegling, Wei Cheng, Hualin Simon Xi, Thomas Werge, Eric Strengman, Susanne Petri, Engilbert Sigurdsson, Mark Hansen, Patrick F. Sullivan, Kieran C. Murphy, Inge Joa, Complex Trait Genetics, McLaughlin, Russell L, Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R, O'Brien, Margaret, Kahn, René S, Ophoff, Roel A, Goris, An, Bradley, Daniel G, Al-Chalabi, Ammar, Van Den Berg, Leonard H, Luykx, Jurjen J, Hardiman, Orla, Veldink, Jan H, Lee, S Hong, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Other departments, Neurology, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Schizophrenia Working Group of the Psychiatric Genomics Consortiumz, Germeys, Inez, Robberecht, Wim, and Van Damme, Philip

Subjects
0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Linkage disequilibrium, Multifactorial Inheritance, General Physics and Astronomy, Genome-wide association study, Comorbidity, VARIANTS, Neurodegenerative, Biochemistry, DISEASE, 3124 Neurology and psychiatry, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Genetics research, Odds Ratio, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, ARCHITECTURE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Chemistry (all), Motor neuron disease, Schizophrenia, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Mental Health, RC0346, motor neuron disease, Project MinE GWAS Consortium, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, Physics and Astronomy (all), Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, MD Multidisciplinary, mental disorders, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Family, Bipolar disorder, GENOME-WIDE ASSOCIATION, Polymorphism, Biology, METAANALYSIS, business.industry, Amyotrophic Lateral Sclerosis, Human Genome, Case-control study, 3112 Neurosciences, Neurosciences, General Chemistry, Odds ratio, medicine.disease, R1, Brain Disorders, 030104 developmental biology, genetics research, Case-Control Studies, RC0321, Linear Models, PLEIOTROPY, Human medicine, 3111 Biomedicine, Biochemistry, Genetics and Molecular Biology (all), ALS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

Published
2017
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5. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Author

Aleksey Shatunov, An Goris, John Hardy, Thomas F. Meyer, Sandra D'Alfonso, Christian A. Hübner, Karol Estrada, Susana Pinto, Cristina Moglia, Perry T.C. van Doormaal, Simona Arcuti, Thomas Meitinger, Siddharthan Chandran, Kim A. Staats, Cinzia Bertolin, Peter M. Andersen, Ricardo Rojas-García, William Sproviero, Katie Sidle, François Salachas, Robert Swingler, Anna M. Blokhuis, Thomas M. Ringer, Emily P. McCann, Garth A. Nicholson, Lude Franke, Sven Cichon, Julian Grosskreutz, Markus M. Nöthen, Bernhard Landwehrmeyer, Lukas Tittmann, Jennifer A. Fifita, Christian R. Andres, Alice Vajda, Viviana Pensato, Lauren Elman, Gijs H.P. Tazelaar, Christian Lunetta, Patrick Vourc'h, Christopher Shaw, Gilbert Bensimon, Orla Hardiman, Kuang Lin, Pamela J. Shaw, Alessandro Padovani, Massimiliano Filosto, Jan H. Veldink, Boris Rogelj, Giacomo P. Comi, Matthew C. Kiernan, Philippe Corcia, Giancarlo Logroscino, Ammar Al-Chalabi, Blaž Koritnik, Safaa Saker-Delye, Ian P. Blair, Alexis Brice, Jochen H. Weishaupt, Gianni Sorarù, Maura Brunetti, Alan M. Pittman, Vincenzo Silani, Cindy Maurel, Alexandra Durr, Catherine Lomen-Hoerth, Matthew R. Robinson, Russell L. McLaughlin, Martina Wiedau-Pazos, Chiara Zecca, Nilo Riva, Ashley R. Jones, Andre Franke, Tune H. Pers, Roberto Del Bo, Dominic B. Rowe, Susanne Petri, Sara L. Pulit, John Q. Trojanowski, Wim Robberecht, Christine Payan, Otto W. Witte, Katharine Y. Zhang, Jesus S. Mora, Rick A.A. van der Spek, Urmo Võsa, Kevin P. Kenna, Marcella Rietschel, Milena Radivojkov-Blagojevic, Tino Prell, Philip Van Damme, Leja Dolenc Grošelj, Androniki Menelaou, Beatrice Stubendorff, Cristina Cereda, Kristel R. van Eijk, Leo McCluskey, Jean-François Dartigues, Rosa Capozzo, Markus Weber, Cinzia Tiloca, Michael A. van Es, Wouter van Rheenen, Paul I.W. de Bakker, Carsten Drepper, Bradley N. Smith, Ettore Beghi, Jian Yang, Peter M. Visscher, Hamid Hamzeiy, John Landers, A. Nazli Basak, Hylke M. Blauw, Annelot M. Dekker, Richard W. Orrell, Silvana Penco, Fernando Rivadeneira, Marianne de Visser, Ceren Tunca, Cathryn M. Lewis, Vincent Meininger, Andrea Malaspina, Raymond D. Schellevis, Leonard H. van den Berg, Rosanna Tortelli, Shuna Colville, Anneke J. van der Kooi, Ingo Kurth, Roger Pamphlett, Stéphanie Millecamps, Janez Zidar, Michael Sendtner, Simone de Jong, Roel A. Ophoff, Mamede de Carvalho, Karen E. Morrison, Robbert Jan Stuit, Letizia Mazzini, Jonathan D. Glass, Yesim Parman, Albert Hofman, Lea Leonardis, Naomi R. Wray, Meraida Polak, William J. Brands, Susanne Abdulla, Bernard Muller, Cinzia Gellera, Max Koppers, Pietro Fratta, John Powell, Charles Curtis, Peter Lichtner, Frank P. Diekstra, Adriano Chiò, Isabella Fogh, Federico Casale, Nicholas W. Wood, Katarina Vrabec, André G. Uitterlinden, Vivianna M. Van Deerlin, Gerome Breen, Wolfgang Lieb, Oliver Harschnitz, Nicola Ticozzi, P. Nigel Leigh, R. Jeroen Pasterkamp, Simon Topp, Metka Ravnik-Glavač, Christophe Tzourio, Robert H. Brown, Andrea Calvo, Orietta Pansarasa, Jelena Medic, Albert C. Ludolph, Elisabetta Pupillo, Antonia Ratti, Philippe Amouyel, Repositório da Universidade de Lisboa, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Erasmus MC other, Pediatric Surgery, Internal Medicine, Epidemiology, Neurology, and ANS - Neurodegeneration

Subjects
0301 basic medicine, Population, EFFICIENT, Genome-wide association study, Locus (genetics), Biology, SUSCEPTIBILITY, SEQUENCE, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Munc18 Proteins, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Comparative Study, Amyotrophic lateral sclerosis, education, POPULATION, Genetic association, Netherlands, PITFALLS, education.field_of_study, HEXANUCLEOTIDE REPEAT, COMPLEX, Project MinE, Amyotrophic Lateral Sclerosis, Proteins, PATHWAYS, FRONTOTEMPORAL DEMENTIA, medicine.disease, Genetic architecture, Cytoskeletal Proteins, 030104 developmental biology, Case-Control Studies, Mutation, ALS, 030217 neurology & neurosurgery, Imputation (genetics), Myelin Proteins, Genome-Wide Association Study
Abstract

Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016
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6. Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis

Author

P. H. C. Kremer, G Je Rinkel, Frank P. Diekstra, B. P. C. Koeleman, L.H. van den Berg, Catharina J.M. Klijn, and Jan H. Veldink

Subjects
Adult, Intracranial Arteriovenous Malformations, Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, Genotype, Interleukin-1beta, Neurogenetics, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Polymorphism (computer science), Angiopoietin-Like Protein 4, Humans, Medicine, SNP, Genetic Predisposition to Disease, Genotyping, Genetics, business.industry, Reproducibility of Results, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Genotype frequency, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Case-Control Studies, Meta-analysis, Cohort, Female, Matrix Metalloproteinase 3, Surgery, Neurology (clinical), business, Angiopoietins, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Item does not contain fulltext BACKGROUND: Case-control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results. METHODS: We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by chi(2) testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3. RESULTS: In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1beta, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005). CONCLUSIONS: The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1beta, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis.

Published
2016

7. No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis

Author

Nigel Leigh, Bénédicte Dubois, Philip L. De Jager, Gabriella Restagno, Vincent Meininger, Wim Robberecht, Gabriele Mora, Michael A. van Es, Orla Hardiman, Ammar Al-Chalabi, Christopher Shaw, Jessica van Setten, Paul I.W. de Bakker, Jorge R. Oksenberg, Bryan J. Traynor, Robert H. Brown, Peter M. Andersen, Philip Van Damme, Leonard H. van den Berg, Nikolaos A. Patsopoulos, Stephen Sawcer, John Landers, An Goris, Alastair Compston, Roel A. Ophoff, Aleksey Shatunov, Stephan Ripke, Jan H. Veldink, Judith Melki, Frank P. Diekstra, and Adriano Chiò

Subjects
Multiple Sclerosis, Genome-wide association study, Single-nucleotide polymorphism, Comorbidity, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, C9orf72, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Molecular Biology, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Multiple sclerosis, Amyotrophic Lateral Sclerosis, Association Studies Articles, General Medicine, medicine.disease, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract

Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.

Published
2014

8. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

Author

Massimo Corbo, Cristina Cereda, Simon Cronin, Carl D. Langefeld, John Landers, Evadnie Rampersaud, Silvana Penco, Stefano Signorini, Jonathan D. Glass, Simon Topp, Gkazi Athina Soraya, Jan H. Veldink, Giancarlo Logroscino, Michael A van Es, Anne Birve, Karen E. Morrison, Davide Gentilini, Robert H. Brown, Paul W.J. van Vught, Jack W. Miller, Franco Taroni, Kreshnik B. Ahmeti, Stefania Corti, Barbara Castellotti, Aldo Quattrone, Senda Ajroud-Driss, Judith Melki, Philip Van Damme, Gabriele Siciliano, Vincent Meininger, Daniela Calini, Julie Williams, Cinzia Gellera, Anne Farmer, Valentina Moskvina, Antonia Ratti, Jonathan L. Haines, John Powell, Giacomo P. Comi, Scott Heller, Sandra D'Alfonso, Nailah Siddique, Margaret A. Pericak-Vance, Angela Marsili, Gabriele Mora, Stella Gagliardi, Peter M. Andersen, Giorgia Querin, Orla Hardiman, Anna Maria Di Blasio, Nicola Ticozzi, Maurizio Inghilleri, Francesco Saccà, Wu-Yen Hung, Cinzia Tiloca, J.G. Zheng, Letizia Mazzini, Mary C. Comeau, Michael E. Weale, James M. Jaworski, Jie Huang, Jennifer Armstrong, Filosto Massimo, Elena Pegoraro, Caroline Vance, Roberto Del Bo, Ewout J N Groen, Teepu Siddique, Nigel Leigh, Lucia Corrado, Josh D. Grab, Mauro Ceroni, Christopher Shaw, Massimiliano Filosto, Alessandra Ferlini, Vincenzo Silani, Adriano Chiò, Sandro Sorbi, Isabella Fogh, Giorgia Puorro, Wenjie Chen, Maria Rosaria Monsurrò, Alessandro Filla, Humaira Khan, Wim Robberecht, Cathryn M. Lewis, Ashley R. Jones, Pensato Viviana, Kuang Lin, Pamela J. Shaw, Ammar Al-Chalabi, Bryan J. Traynor, Leonard H. van den Berg, Michael Sendtner, Vincenzo Brescia Morra, Aleksey Shatunov, Frank P. Diekstra, Vincenzo La Bella, Gianni Sorarù, Robert L. Sufit, Daniel J. Overste, Yi Yang, Paolo Bongioanni, Miranda C. Marion, Bradley N. Smith, Francesca Luisa Conforti, Hylke M. Blauw, Lucie Bruijn, Isabella Laura Simone, Russell L. McLaughlin, Fogh, I., Ratti, A., Gellera, C., Lin, K., Tiloca, C., Moskvina, V., Corrado, L., Sorarù, G., Cereda, C., Corti, S., Gentilini, D., Calini, D., Castellotti, B., Mazzini, L., Querin, G., Gagliardi, S., Bo, R. D., Conforti, F. L., Siciliano, G., Inghilleri, M., Sacca', Francesco, Bongioanni, P., Penco, S., Corbo, M., Sorbi, S., Filosto, M., Ferlini, A., Di, A. M., Signorini, S., Shatunov, A., Jones, A., Shaw, P. J., Morrison, K. E., Farmer, A. E., Damme, P. V., Robberecht, W., Chiò, A., Traynor, B. J., Sendtner, M., Melki, J., Meininger, V., Hardiman, O., Andersen, P. M., Leigh, N. P., Glass, J. D., Overste, D., Diekstra, F. P., Veldink, J. H., Van, M. A., Shaw, C. E., Weale, M. E., Lewis, C. M., Williams, J., Brown, R. H., Landers, J. E., Ticozzi, N., Ceroni, M., Pegoraro, E., Comi, G. P., D'Alfonso, S., Van, L. H., Taroni, F., Al-Chalabi, A., Powell, J., Silani, V., S., T., S., Consortium, and Filla, Alessandro

Subjects
genetic structures, Prognosi, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Chromosomes, 03 medical and health sciences, 0302 clinical medicine, Genotype, Genetics, medicine, Humans, Amyotrophic lateral sclerosis, Molecular Biology, Genetics (clinical), 030304 developmental biology, amyotrophic lateral sclerosis, genetic, 0303 health sciences, Amyotrophic Lateral Sclerosis, Case-Control Studies, Chromosomes, Human, Pair 17, Prognosis, Genome-Wide Association Study, Pair 17, Association Studies Articles, Case-control study, General Medicine, Heritability, medicine.disease, 3. Good health, Case-Control Studie, 030217 neurology & neurosurgery, Imputation (genetics), Amyotrophic Lateral Sclerosi, Human
Abstract

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

Published
2013
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9. Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS

Author

Orla Hardiman, Albert Hofman, Wouter van Rheenen, Michael A. van Es, Ritsert C. Jansen, Frank P. Diekstra, Christopher Shaw, John Landers, Karol Estrada, Wim Robberecht, Steve Horvath, Ammar Al-Chalabi, Vincent Meininger, Hylke M. Blauw, Fernando Rivadeneira, Judith Melki, André G. Uitterlinden, P. Nigel Leigh, Robert H. Brown, Leonard H. van den Berg, Roel A. Ophoff, Aleksey Shatunov, Christiaan G J Saris, Peter M. Andersen, Ewout J N Groen, Jan H. Veldink, Lude Franke, Paul W.J. van Vught, Internal Medicine, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Bioinformatics, Stem Cell Aging Leukemia and Lymphoma (SALL), and van der Brug, Marcel P

Subjects
Candidate gene, Linkage disequilibrium, Neurologi, Gene Expression, lcsh:Medicine, Genome-wide association study, Neurodegenerative, VARIANTS, AMYOTROPHIC-LATERAL-SCLEROSIS, Linkage Disequilibrium, Motor Neuron Diseases, 0302 clinical medicine, 2.1 Biological and endogenous factors, TOOL, Aetiology, Cytochrome P-450 CYP27A1, lcsh:Science, RISK, Motor Neurons, Genetics, 0303 health sciences, Multidisciplinary, Neurodegenerative Diseases, Xanthomatosis, Cerebrotendinous, Genomics, Single Nucleotide, CROHNS-DISEASE, Pedigree, Neurology, RC0346, Neurological, Medicine, Cholestanetriol 26-Monooxygenase, Biotechnology, Research Article, Genotype, General Science & Technology, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), HapMap Project, Biology, Quantitative trait locus, DIAGNOSIS, Polymorphism, Single Nucleotide, 03 medical and health sciences, Rare Diseases, Genome Analysis Tools, Genome-Wide Association Studies, Xanthomatosis, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Polymorphism, 030304 developmental biology, Genetic association, Cerebrotendinous, HEXANUCLEOTIDE REPEAT, MUTATIONS, Gene Expression Profiling, Human Genome, lcsh:R, Amyotrophic Lateral Sclerosis, Neurosciences, Computational Biology, Human Genetics, Brain Disorders, Genetics of Disease, Expression quantitative trait loci, lcsh:Q, ALS, Genome Expression Analysis, CEREBROTENDINOUS XANTHOMATOSIS, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS. ispartof: PLoS One vol:7 issue:4 ispartof: location:United States status: published

Published
2012
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10. A large genome scan for rare CNVs in amyotrophic lateral sclerosis

Author

Eric Strengman, Ruben van 't Slot, Peter C. Sapp, Thomas F. Meyer, Anna Birve, Peter M. Andersen, Martin D. Tobin, Max Koppers, Ewout J N Groen, Albert C. Ludolph, Simon Cronin, Sita H. Vermeulen, Claudia Schulte, Jan H. Veldink, André G. Uitterlinden, Robin Lemmens, Paul W.J. van Vught, Thomas Gasser, Lambertus A. Kiemeney, Christiaan G J Saris, Hylke M. Blauw, Leonard H. van den Berg, Frank P. Diekstra, Fernando Rivadeneira, Karol Estrada, Robert H. Brown, Agnieszka Slowik, Barbara Tomik, Louise V. Wain, Russell L. McLaughlin, Dan Rujescu, Michael A. van Es, Albert Hofman, Wim Robberecht, Ammar Al-Chalabi, Wouter van Rheenen, John Landers, Orla Hardiman, Roel A. Ophoff, Stefan Waibel, Internal Medicine, and Epidemiology

Subjects
Potassium Channels, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], Polymerase Chain Reaction, genetics [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases], 0302 clinical medicine, Risk Factors, Copy-number variation, Amyotrophic lateral sclerosis, genetics [Nerve Tissue Proteins], NIPA1 protein, human, Genetics (clinical), Motor Neurons, Genetics, 0303 health sciences, education.field_of_study, genetics [Potassium Channels], DPP6 protein, human, General Medicine, 3. Good health, genetics [Amyotrophic Lateral Sclerosis], genetics [Membrane Proteins], DNA Copy Number Variations, Population, Nerve Tissue Proteins, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, ddc:570, genetics [Spastic Paraplegia, Hereditary], medicine, Humans, Genetic Predisposition to Disease, Allele, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, education, Molecular Biology, 030304 developmental biology, Genetic association, Genome, Human, Spastic Paraplegia, Hereditary, Amyotrophic Lateral Sclerosis, Genetic Variation, Membrane Proteins, medicine.disease, Evaluation of complex medical interventions [NCEBP 2], Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 89076.pdf (Publisher’s version ) (Closed access) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 x 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 x 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 x 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 x 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.

Published
2010
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11. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation

Author

Dick Lindhout, E. Strengman, Frank Baas, Pierre R. Bourque, Frank P. Diekstra, Eric A. M. Hennekam, Roel A. Ophoff, J. H. Veldink, Helenius J. Schelhaas, L. H. van den Berg, M. A. van Es, Amsterdam Neuroscience, Neurology, and Genome Analysis

Subjects
Male, Heterozygote, SOD1, Population, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Perception and Action [DCN 1], Medicine, Humans, Amino Acid Sequence, Amyotrophic lateral sclerosis, Isoleucine, education, Peptide sequence, Gene, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), 030304 developmental biology, Aged, Genetics, 0303 health sciences, Mutation, education.field_of_study, Base Sequence, business.industry, Lysine, Amyotrophic Lateral Sclerosis, Ribonuclease, Pancreatic, VAPB, Middle Aged, medicine.disease, 3. Good health, Pedigree, Amino Acid Substitution, Mutation testing, Dementia, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Approximately 90% of amyotrophic lateral sclerosis (ALS) cases are sporadic (SALS), but 10% are familial (FALS). Mutations in SOD1, Alsin , Dynactin , SETX , DJ-1 , VAPB , and TDP-431 have been reported (table e-1 on the Neurology ® Web site at www.neurology.org). After the identification of sequence variation VEGF in patients with ALS, mutations in another angiogenic gene ( ANG ) were identified in SALS and FALS.2,3 Studies in other populations have identified ANG mutations in patients with ALS, but also in healthy controls. This suggests that not all mutations are pathogenic.3,4 ### Methods. A total of 39 unrelated FALS patients, negative for SOD1 mutations, were screened for ANG mutations. This study was approved by the local ethics committee and participants provided informed consent. DNA was isolated from venous blood and ANG mutation analysis was performed as described in appendix e-1. A total of 275 unrelated, healthy controls were taken from a prospective population-based study on ALS in The Netherlands and were also screened.5 PMut (http://mmb2.pcb.ub.es:8080/PMut/) was used to predict the impact of an amino acid substitution on the structure and function of the protein. ### Results. We identified one mutation in one patient (122 A>T) (figure, A), leading to an amino acid substitution of lysine to isoleucine (K17I) (figure, B). PMut analysis predicted this mutation to be pathogenic. Sequence alignments of ANG in different species …

Published
2009

12. Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1

Author

Kreshnik B, Ahmeti, Senda, Ajroud-Driss, Ammar, Al-Chalabi, Peter M, Andersen, Jennifer, Armstrong, Anne, Birve, Hylke M, Blauw, Robert H, Brown, Lucie, Bruijn, Wenjie, Chen, Adriano, Chio, Mary C, Comeau, Simon, Cronin, Frank P, Diekstra, Athina, Soraya Gkazi, Jonathan D, Glass, Josh D, Grab, Ewout J, Groen, Jonathan L, Haines, Orla, Hardiman, Scott, Heller, Jie, Huang, Wu-Yen, Hung, James M, Jaworski, Ashley, Jones, Humaira, Khan, John E, Landers, Carl D, Langefeld, P Nigel, Leigh, Miranda C, Marion, Russell L, McLaughlin, Vincent, Meininger, Judith, Melki, Jack W, Miller, Gabriele, Mora, Margaret A, Pericak-Vance, Evadnie, Rampersaud, Wim, Robberecht, Laurie P, Russell, Francois, Salachas, Christiaan G, Saris, Aleksey, Shatunov, Christopher E, Shaw, Nailah, Siddique, Teepu, Siddique, Bradley N, Smith, Robert, Sufit, Simon, Topp, Bryan J, Traynor, Caroline, Vance, Philip, van Damme, Leonard H, van den Berg, Michael A, van Es, Paul W, van Vught, Jan H, Veldink, Yi, Yang, and J G, Zheng

Subjects
Male, Oncology, Aging, medicine.medical_specialty, Genotype, Locus (genetics), Disease, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Internal medicine, medicine, Paralysis, Humans, genetics, Genetic Predisposition to Disease, Age of Onset, Amyotrophic lateral sclerosis, prognostic factor, Aged, 030304 developmental biology, Aged, 80 and over, Genetics, 0303 health sciences, General Neuroscience, Amyotrophic Lateral Sclerosis, Odds ratio, Middle Aged, medicine.disease, United States, 3. Good health, Europe, Minor allele frequency, Chromosomes, Human, Pair 1, Female, Neurology (clinical), Geriatrics and Gerontology, Age of onset, medicine.symptom, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.

Published
2013
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13. H63D polymorphism in HFE is not associated with amyotrophic lateral sclerosis

Author

Aleksey Shatunov, Karen E. Morrison, Kevin P. Kenna, Markus Weber, Christopher Shaw, Frank P. Diekstra, David Czell, Perry T.C. van Doormaal, Meinie Seelen, Wouter van Rheenen, Michael A. van Es, Anneke J. van der Kooi, Wim Robberecht, Bradley N. Smith, H. Jurgen Schelhaas, Leonard H. van den Berg, Marianne de Visser, Pamela J. Shaw, Ammar Al-Chalabi, Peter M. Andersen, Albert C. Ludolph, Russell L. McLaughlin, Stefan Waibel, Jan H. Veldink, Paul W.J. van Vught, Philip Van Damme, Orla Hardiman, ANS - Amsterdam Neuroscience, and Neurology

Subjects
Adult, Genetic Markers, Male, Aging, medicine.medical_specialty, Pathology, congenital, hereditary, and neonatal diseases and abnormalities, Disease onset, Neurology, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Prevalence, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Hemochromatosis Protein, Aged, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, Histocompatibility Antigens Class I, Membrane Proteins, nutritional and metabolic diseases, Middle Aged, Control subjects, medicine.disease, Europe, Genetic marker, Meta-analysis, Cohort, Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival. ispartof: Neurobiology of aging vol:34 issue:5 pages:1517- ispartof: location:United States status: published

Published
2013
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14. CGG-repeat expansion in FMR1 is not associated with amyotrophic lateral sclerosis

Author

Max Koppers, Frank P. Diekstra, R. Jeroen Pasterkamp, Lotte Vlam, Perry T.C. van Doormaal, Ewout J N Groen, Leonard H. van den Berg, Jan H. Veldink, Dennis Dooijes, and Wouter van Rheenen

Subjects
Genetic Markers, Male, congenital, hereditary, and neonatal diseases and abnormalities, Aging, Ataxia, Polymorphism, Single Nucleotide, Fragile X Mental Retardation Protein, 03 medical and health sciences, Exon, 0302 clinical medicine, Risk Factors, C9orf72, Prevalence, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Genetic Association Studies, Aged, Netherlands, Repetitive Sequences, Nucleic Acid, 030304 developmental biology, Aged, 80 and over, Genetics, 0303 health sciences, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, Genetic Variation, Middle Aged, medicine.disease, FMR1, nervous system diseases, Spinocerebellar ataxia, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, Trinucleotide repeat expansion, business, 030217 neurology & neurosurgery, Developmental Biology, Frontotemporal dementia
Abstract

Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS.

Published
2012
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15. UNC13A is a modifier of survival in amyotrophic lateral sclerosis

Author

Paul W.J. van Vught, R. Jeroen Pasterkamp, Wim Robberecht, Philip Van Damme, Peter M. Andersen, Leonard H. van den Berg, Wouter van Rheenen, Frank P. Diekstra, Michael A. van Es, Max Koppers, Helenius J. Schelhaas, Marianne de Visser, Jan H. Veldink, and Neurology

Subjects
Oncology, Adult, Male, Aging, medicine.medical_specialty, Pathology, Adolescent, Population, Nerve Tissue Proteins, Disease, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, education, Survival analysis, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, education.field_of_study, business.industry, General Neuroscience, Amyotrophic Lateral Sclerosis, Case-control study, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Minor allele frequency, Case-Control Studies, Cohort, Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis. (C) 2012 Elsevier Inc. All rights reserved

Published
2012
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16. Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis

Author

Philip Van Damme, Kristel R. van Eijk, Albert C. Ludolph, Jesus S. Mora Pardina, Wim Robberecht, Orla Hardiman, Rick A.A. van der Spek, Andrea Calvo, Jochen H. Weishaupt, Leonard H. van den Berg, Gijs H.P. Tazelaar, Maura Brunetti, Russell L. McLaughlin, Jan H. Veldink, Frank P. Diekstra, Sara L. Pulit, Adriano Chiò, Michael Sendtner, Annelot M. Dekker, and Wouter van Rheenen

Subjects
0301 basic medicine, lcsh:Medicine, Disease, 0302 clinical medicine, Exome, Amyotrophic lateral sclerosis, lcsh:Science, Genetics, Multidisciplinary, GENETIC-VARIATION, ASSOCIATION, 3. Good health, Multidisciplinary Sciences, Phenotype, Science & Technology - Other Topics, Genetic Markers, STRATEGIES, Genotype, POWER, C9ORF72, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Exome Sequencing, LINKAGE, INJURY, Journal Article, medicine, PLINK, Humans, Genetic Predisposition to Disease, General, Genotyping, Gene, Genetic Association Studies, Genetic association, Science & Technology, HEXANUCLEOTIDE REPEAT, ANALYSES IDENTIFY, lcsh:R, Amyotrophic Lateral Sclerosis, Heritability, medicine.disease, Genetic architecture, 030104 developmental biology, Case-Control Studies, lcsh:Q, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS. ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published

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