Novel Gene Associated With ALS Identified

Summary: A new study reveals three new genes associated with ALS. One of the genes, C21orf2, could increase a person’s risk of developing ALS by 65 percent.

Source: King’s College London.

Published today in Nature Genetics, the study reveals three new risk genes for ALS and one of these – C21orf2 – increases an individual’s risk of developing the disease by 65 percent. These results could aid the development of personalised treatments for people with ALS by using gene therapy – an approach which involves replacing faulty genes or adding new ones.

One in every 400 people will be diagnosed with amyotrophic lateral sclerosis (ALS) at some point in their lives, yet its causes are largely unknown and effective treatments are therefore lacking.

In ALS, motor neurons in the brain and spinal cord degenerate causing the muscles they control to weaken and waste away. Symptoms normally start in mid-life and eventually affect all movement including swallowing and breathing. Average life expectancy from symptom onset is two to five years.

Variations of the genes we all carry are an important cause of ALS, even though most people do not have an inherited form of the condition. The researchers set out to discover new genes for ALS to find out why the disease develops and how to design new treatments.

Using genetic data from Project MinE, comprising 15,156 ALS patients and 26,224 healthy controls from 15 countries, the researchers combined ‘snapshot’ genetic information with whole genome sequencing of 1,861 individuals. Whole genome sequencing involves reading every single one of the six billion letters in the human genome. In total 8,697,640 variants across the genome were tested for the risk of developing ALS.

The researchers identified three new risk genes for ALS. One of these, called C21orf2, appeared to be particularly important as a risk factor for ALS. The exact function of C21orf2 is still unknown, but it appears to be part of a system in cells related to their own movement and their internal skeleton. They also found that for any one person, just one or two genes had a substantial effect on whether they developed ALS, which is different from most other conditions in which lots of genes each have a small effect.

Professor Ammar Al-Chalabi from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, said: ‘This tells us that ALS is not the result of a few common gene variations that each contribute a little to the risk. Rather, any one of many rare gene variations contributes a large risk for ALS development. This insight is crucial as it affects the types of treatment strategies that might be effective.’

Image shows a DNA double helix.
Variations of the genes we all carry are an important cause of ALS, even though most people do not have an inherited form of the condition. The researchers set out to discover new genes for ALS to find out why the disease develops and how to design new treatments. NeuroscienceNews.com image is for illustrative purposes only.

Professor Jan Veldink from the University Medical Center Utrecht said: ‘Most genetics studies in ALS focus on the familial form of the disease. Project MinE is an innovative approach to find genetic causes of all ALS cases. In this study we have found a total of three genomic regions where genetic variation in these regions increases the risk of ALS. One of these regions included a gene named C21orf2. This gene was subsequently shown to harbour rare mutations that directly increase ALS risk. This makes the C21orf2 gene extremely interesting for future studies to shed light on the mechanisms that lead to ALS and possibly future therapeutic strategies.’

Professor Ammar Al-Chalabi added: ‘Pinpointing genes which increase the risk of ALS will help us develop new treatments that can stop or improve symptoms of ALS in the future. The more we understand about the genetic basis of ALS, the closer we are to revealing new treatment targets and effective therapies.’

Brian Dickie, Director of Research Development at the Motor Neurone Disease (MND) Association said: ‘We are pleased to have been involved since this approach to gene hunting was in its infancy a decade ago. It’s so encouraging to see how the collaboration, catalysed by Project MinE, has grown and is now delivering results that will open up new avenues of research across the world.’

About this ALS research article

Funding: The study was funded by the Motor Neurone Disease (MND) Association, Project MinE, the ALS Association and the EU Joint Programme on Neurodegeneration Research through the Medical Research Council (funding of the STRENGTH European consortium).

Source: Louise Pratt – King’s College London
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis” by Wouter van Rheenen, Aleksey Shatunov, Annelot M Dekker, Russell L McLaughlin, Frank P Diekstra, Sara L Pulit, Rick A A van der Spek, Urmo Võsa, Simone de Jong, Matthew R Robinson, Jian Yang, Isabella Fogh, Perry TC van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M Blokhuis, William Sproviero, Ashley R Jones, Kevin P Kenna, Kristel R van Eijk, Oliver Harschnitz, Raymond D Schellevis, William J Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, Metka Ravnik-Glavač, Blaž Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Jesus S Mora, Ricardo Rojas-García, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen E Morrison, Pamela J Shaw, John Hardy, Richard W Orrell, Alan Pittman, Katie Sidle, Pietro Fratta, Andrea Malaspina, Simon Topp, Susanne Petri, Susanne Abdulla, Carsten Drepper, Michael Sendtner, Thomas Meyer, Roel A Ophoff, Kim A Staats, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna M Van Deerlin, John Q Trojanowski, Lauren Elman, Leo McCluskey, A Nazli Basak, Ceren Tunca, Hamid Hamzeiy, Yesim Parman, Thomas Meitinger, Peter Lichtner, Milena Radivojkov-Blagojevic, Christian R Andres, Cindy Maurel, Gilbert Bensimon, Bernhard Landwehrmeyer, Alexis Brice, Christine A M Payan, Safaa Saker-Delye, Alexandra Dürr, Nicholas W Wood, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Marcella Rietschel, Sven Cichon, Markus M Nöthen, Philippe Amouyel, Christophe Tzourio, Jean-François Dartigues, Andre G Uitterlinden, Fernando Rivadeneira, Karol Estrada, Albert Hofman, Charles Curtis, Hylke M Blauw, Anneke J van der Kooi, Wim Robberecht, Ian Blair, Cristina Moglia, John Powell, Roger Pamphlett, Bradley N Smith, Philippe Corcia, Ammar Al-Chalabi, PARALS Registry, Emily P McCann, Garth A Nicholson, Letizia Mazzini, Andrea Calvo, Beatrice Stubendorff, Alessandro Padovani, Ettore Beghi, Giacomo P Comi, Leonard H van den Berg, NNIPPS Study Group, Antonia Ratti, Peter M Visscher, Tino Prell, Orla Hardiman, Jan H Veldink, Marianne de Visser, Otto W Witte, Jochen H Weishaupt, Katharine Zhang, Matthew C Kiernan, Vincenzo Silani, SLAP Registry, Rosanna Tortelli, Christian Lunetta, Nilo Riva, Massimiliano Filosto, An Goris, Federico Casale, Patrick Vourc’h, Paul I W de Bakker, Roberto Del Bo, Peter M Andersen, Orietta Pansarasa, Cinzia Gellera, Cathryn M Lewis, Michael A van Es, P Nigel Leigh, SLALOM Group, John E Landers, Rosa Capozzo, Robert H Brown, Philip Van Damme, Robbert Jan Stuit, Thomas Ringer, Giancarlo Logroscino, Jonathan D Glass, Cinzia Bertolin, Bernard Muller, Dominic B Rowe, Albert C Ludolph, Markus Weber, SLAGEN Consortium, Cristina Cereda, Lude Franke, Cinzia Tiloca, Gianni Sorarù, Julian Grosskreutz, Jennifer A Fifita, Adriano Chio, Christopher E Shaw, Maura Brunetti, Tune H Pers, Ingo Kurth, Gerome Breen, Viviana Pensato, Naomi R Wray, Chiara Zecca, Silvana Penco, Elisabetta Pupillo, Sandra D’Alfonso, R Jeroen Pasterkamp, Christian A Hübner, Simona Arcuti and FALS Sequencing Consortium in Nature Genetics. Published online July 25 2016 doi:10.1038/ng.3622

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]King’s College London. “Novel Gene Associated With ALS Identified.” NeuroscienceNews. NeuroscienceNews, 26 July 2016.
<https://neurosciencenews.com/c21orf2-als-genetics-4734/>.[/cbtab][cbtab title=”APA”]King’s College London. (2016, July 26). Novel Gene Associated With ALS Identified. NeuroscienceNews. Retrieved July 26, 2016 from https://neurosciencenews.com/c21orf2-als-genetics-4734/[/cbtab][cbtab title=”Chicago”]King’s College London. “Novel Gene Associated With ALS Identified.” https://neurosciencenews.com/c21orf2-als-genetics-4734/ (accessed July 26, 2016).[/cbtab][/cbtabs]


Abstract

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

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.

“Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis” by Wouter van Rheenen, Aleksey Shatunov, Annelot M Dekker, Russell L McLaughlin, Frank P Diekstra, Sara L Pulit, Rick A A van der Spek, Urmo Võsa, Simone de Jong, Matthew R Robinson, Jian Yang, Isabella Fogh, Perry TC van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M Blokhuis, William Sproviero, Ashley R Jones, Kevin P Kenna, Kristel R van Eijk, Oliver Harschnitz, Raymond D Schellevis, William J Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, Metka Ravnik-Glavač, Blaž Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Jesus S Mora, Ricardo Rojas-García, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen E Morrison, Pamela J Shaw, John Hardy, Richard W Orrell, Alan Pittman, Katie Sidle, Pietro Fratta, Andrea Malaspina, Simon Topp, Susanne Petri, Susanne Abdulla, Carsten Drepper, Michael Sendtner, Thomas Meyer, Roel A Ophoff, Kim A Staats, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna M Van Deerlin, John Q Trojanowski, Lauren Elman, Leo McCluskey, A Nazli Basak, Ceren Tunca, Hamid Hamzeiy, Yesim Parman, Thomas Meitinger, Peter Lichtner, Milena Radivojkov-Blagojevic, Christian R Andres, Cindy Maurel, Gilbert Bensimon, Bernhard Landwehrmeyer, Alexis Brice, Christine A M Payan, Safaa Saker-Delye, Alexandra Dürr, Nicholas W Wood, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Marcella Rietschel, Sven Cichon, Markus M Nöthen, Philippe Amouyel, Christophe Tzourio, Jean-François Dartigues, Andre G Uitterlinden, Fernando Rivadeneira, Karol Estrada, Albert Hofman, Charles Curtis, Hylke M Blauw, Anneke J van der Kooi, Wim Robberecht, Ian Blair, Cristina Moglia, John Powell, Roger Pamphlett, Bradley N Smith, Philippe Corcia, Ammar Al-Chalabi, PARALS Registry, Emily P McCann, Garth A Nicholson, Letizia Mazzini, Andrea Calvo, Beatrice Stubendorff, Alessandro Padovani, Ettore Beghi, Giacomo P Comi, Leonard H van den Berg, NNIPPS Study Group, Antonia Ratti, Peter M Visscher, Tino Prell, Orla Hardiman, Jan H Veldink, Marianne de Visser, Otto W Witte, Jochen H Weishaupt, Katharine Zhang, Matthew C Kiernan, Vincenzo Silani, SLAP Registry, Rosanna Tortelli, Christian Lunetta, Nilo Riva, Massimiliano Filosto, An Goris, Federico Casale, Patrick Vourc’h, Paul I W de Bakker, Roberto Del Bo, Peter M Andersen, Orietta Pansarasa, Cinzia Gellera, Cathryn M Lewis, Michael A van Es, P Nigel Leigh, SLALOM Group, John E Landers, Rosa Capozzo, Robert H Brown, Philip Van Damme, Robbert Jan Stuit, Thomas Ringer, Giancarlo Logroscino, Jonathan D Glass, Cinzia Bertolin, Bernard Muller, Dominic B Rowe, Albert C Ludolph, Markus Weber, SLAGEN Consortium, Cristina Cereda, Lude Franke, Cinzia Tiloca, Gianni Sorarù, Julian Grosskreutz, Jennifer A Fifita, Adriano Chio, Christopher E Shaw, Maura Brunetti, Tune H Pers, Ingo Kurth, Gerome Breen, Viviana Pensato, Naomi R Wray, Chiara Zecca, Silvana Penco, Elisabetta Pupillo, Sandra D’Alfonso, R Jeroen Pasterkamp, Christian A Hübner, Simona Arcuti and FALS Sequencing Consortium in Nature Genetics. Published online July 25 2016 doi:10.1038/ng.3622

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