npj Genomic Medicine (Jan 2022)
Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis
- Ahmad Al Khleifat,
- Alfredo Iacoangeli,
- Joke J. F. A. van Vugt,
- Harry Bowles,
- Matthieu Moisse,
- Ramona A. J. Zwamborn,
- Rick A. A. van der Spek,
- Aleksey Shatunov,
- Johnathan Cooper-Knock,
- Simon Topp,
- Ross Byrne,
- Cinzia Gellera,
- Victoria López,
- Ashley R. Jones,
- Sarah Opie-Martin,
- Atay Vural,
- Yolanda Campos,
- Wouter van Rheenen,
- Brendan Kenna,
- Kristel R. Van Eijk,
- Kevin Kenna,
- Markus Weber,
- Bradley Smith,
- Isabella Fogh,
- Vincenzo Silani,
- Karen E. Morrison,
- Richard Dobson,
- Michael A. van Es,
- Russell L. McLaughlin,
- Patrick Vourc’h,
- Adriano Chio,
- Philippe Corcia,
- Mamede de Carvalho,
- Marc Gotkine,
- Monica P. Panades,
- Jesus S. Mora,
- Pamela J. Shaw,
- John E. Landers,
- Jonathan D. Glass,
- Christopher E. Shaw,
- Nazli Basak,
- Orla Hardiman,
- Wim Robberecht,
- Philip Van Damme,
- Leonard H. van den Berg,
- Jan H. Veldink,
- Ammar Al-Chalabi
Affiliations
- Ahmad Al Khleifat
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Alfredo Iacoangeli
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Joke J. F. A. van Vugt
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Harry Bowles
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Matthieu Moisse
- KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology
- Ramona A. J. Zwamborn
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Rick A. A. van der Spek
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Aleksey Shatunov
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Johnathan Cooper-Knock
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield
- Simon Topp
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Ross Byrne
- Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin
- Cinzia Gellera
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano
- Victoria López
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano
- Ashley R. Jones
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Sarah Opie-Martin
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Atay Vural
- Koc University, School of Medicine, Translational Medicine Research Center- NDAL
- Yolanda Campos
- Mitochondrial pathology Unit, Instituto de Salud Carlos III
- Wouter van Rheenen
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Brendan Kenna
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Kristel R. Van Eijk
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Kevin Kenna
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Markus Weber
- Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen
- Bradley Smith
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Isabella Fogh
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Vincenzo Silani
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano
- Karen E. Morrison
- Faculty of Medicine, Health and Life Sciences, Queen’s University Belfast
- Richard Dobson
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Michael A. van Es
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Russell L. McLaughlin
- Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin
- Patrick Vourc’h
- Centre SLA, CHRU de Tours
- Adriano Chio
- Rita Levi Montalcini, Department of Neuroscience, ALS Centre, University of Torino
- Philippe Corcia
- Centre SLA, CHRU de Tours
- Mamede de Carvalho
- Physiology Institute, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon
- Marc Gotkine
- Hadassah University Hospital
- Monica P. Panades
- Neurology Department, Hospital Universitari de Bellvitge
- Jesus S. Mora
- Hospital San Rafael
- Pamela J. Shaw
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield
- John E. Landers
- Department of Neurology, University of Massachusetts Medical School
- Jonathan D. Glass
- Department of Neurology, Center for Neurodegenerative Diseases, Emory University
- Christopher E. Shaw
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- Nazli Basak
- Koc University, School of Medicine, Translational Medicine Research Center- NDAL
- Orla Hardiman
- Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute
- Wim Robberecht
- KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology
- Philip Van Damme
- KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology
- Leonard H. van den Berg
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Jan H. Veldink
- Department of Neurology, UMC Utrecht Brain Center, Utrecht University
- Ammar Al-Chalabi
- King’s College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park
- DOI
- https://doi.org/10.1038/s41525-021-00267-9
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 8
Abstract
Abstract There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.
