ArticleNPJ genomic medicine2022
Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis.
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Article in NPJ genomic medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26citing papers in PubMed
5.1field-weighted citation impact, top 4% of its field
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26 citing papers in PubMed, 43 citations in OpenAlex.
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- Entering the era of precision medicine to treat amyotrophic lateral sclerosis.Molecular neurodegeneration · 2025Review
- Genetic analysis ofFrontiers in aging neuroscience · 2025Article
- Retrotransposition-competent L1s are increased in the genomes of individuals with amyotrophic lateral sclerosis.Experimental biology and medicine (Maywood, N.J.) · 2025Article
- Scrutinizing neurodegenerative diseases: decoding the complex genetic architectures through a multi-omics lens.Human genomics · 2024Review
- Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.Cell genomics · 2024Article
- Increased copy-number variant load of associated risk genes in sporadic cases of amyotrophic lateral sclerosis.Cellular and molecular life sciences : CMLS · 2024Article
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- The Role of Structural Variants in the Genetic Architecture of Parkinson's Disease.International journal of molecular sciences · 2024Review
- Distribution of theFrontiers in neurology · 2024Article
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- Amyotrophic lateral sclerosis: translating genetic discoveries into therapies.Nature reviews. Genetics · 2023Review
- Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans.Neurology. Genetics · 2023Article
- In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Article
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- Advances in sequencing technologies for amyotrophic lateral sclerosis research.Molecular neurodegeneration · 2023Review
- VariantSurvival: a tool to identify genotype-treatment response.Frontiers in bioinformatics · 2023Article
- The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases.International journal of molecular sciences · 2022Review
- Singling out motor neurons in the age of single-cell transcriptomics.Trends in genetics : TIG · 2022Review
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Authors and funding
47 authors at 18 institutions in 12 countries.
Ahmad Al KhleifatKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.ORCID http://orcid.org/0000-0002-7406-9831
Alfredo IacoangeliKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Joke J F A van VugtDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Harry BowlesKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Matthieu MoisseKU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.ORCID http://orcid.org/0000-0001-8880-9311
Ramona A J ZwambornDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Rick A A van der SpekDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0001-9983-204X
Aleksey ShatunovKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Johnathan Cooper-KnockSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Simon ToppKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Ross ByrneComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.ORCID http://orcid.org/0000-0002-4082-6072
Cinzia GelleraDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy.
Victoria LópezDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy.ORCID http://orcid.org/0000-0001-8129-8352
Ashley R JonesKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.ORCID http://orcid.org/0000-0003-0470-0058
Sarah Opie-MartinKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Atay VuralKoc University, School of Medicine, Translational Medicine Research Center- NDAL, Istanbul, Turkey.
Yolanda CamposMitochondrial pathology Unit, Instituto de Salud Carlos III, Madrid, Spain.
Wouter van RheenenDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0002-5860-1533
Brendan KennaDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0001-7591-2221
Kristel R Van EijkDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Kevin KennaDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Markus WeberNeuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Bradley SmithKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Isabella FoghKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Vincenzo SilaniDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano and Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy.
Karen E MorrisonFaculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.ORCID http://orcid.org/0000-0003-0216-5717
Richard DobsonDepartment of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.ORCID http://orcid.org/0000-0003-4224-9245
Michael A van EsDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0002-7709-5883
Russell L McLaughlinComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.ORCID http://orcid.org/0000-0003-3915-2135
Patrick Vourc'hCentre SLA, CHRU de Tours, Tours, France.
Adriano ChioRita Levi Montalcini, Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.ORCID http://orcid.org/0000-0001-9579-5341
Philippe CorciaCentre SLA, CHRU de Tours, Tours, France.
Mamede de CarvalhoPhysiology Institute, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal.ORCID http://orcid.org/0000-0001-7556-0158
Marc GotkineHadassah University Hospital, Jerusalem, Israel.ORCID http://orcid.org/0000-0003-2541-6232
Monica P PanadesNeurology Department, Hospital Universitari de Bellvitge, Barcelona, Spain.
Jesus S MoraHospital San Rafael, Madrid, Spain.ORCID http://orcid.org/0000-0001-6633-5354
Pamela J ShawSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
John E LandersDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.ORCID http://orcid.org/0000-0001-8084-5043
Jonathan D GlassDepartment of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA.ORCID http://orcid.org/0000-0002-3295-4971
Christopher E ShawKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
Nazli BasakKoc University, School of Medicine, Translational Medicine Research Center- NDAL, Istanbul, Turkey.
Orla HardimanAcademic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland.
Wim RobberechtKU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
Philip Van DammeKU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.ORCID http://orcid.org/0000-0002-4010-2357
Leonard H van den BergDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Jan H VeldinkDepartment of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0001-5572-9657
Ammar Al-ChalabiKing's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK. ammar.al-chalabi@kcl.ac.uk.ORCID http://orcid.org/0000-0002-4924-7712
King's College London · GBUtrecht University · NLTrinity College Dublin · IEUniversity of Milan · ITVIB-KU Leuven Center for Brain & Disease Research · BECentre Hospitalier Universitaire de Tours · FRKoç University · TRUniversity of Sheffield · GBAzienda Ospedaliera Citta' della Salute e della Scienza di Torino · ITBellvitge University Hospital · ESEmory University · USHadassah Academic College · ILHospital Universitario San Rafael · ESInstituto de Salud Carlos III · ESKantonsspital St. Gallen · CHQueen's University Belfast · GBUniversity of Lisbon · PTUniversity of Massachusetts Chan Medical School · US
Funding
Identification of genes causative for familial ALS gene using exome sequencingR01NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2011 to 2019
$4.6MIdentification and Characterization of ALS/FTD Associated Variants Using Whole Genome SequencingR56NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2020 to 2020
$586kMedical Research Council G0300329Medical Research Council G0500289Medical Research Council G0600974Medical Research Council G0900635Medical Research Council G0900688Medical Research Council G1100695Medical Research Council MC_PC_17115Medical Research Council MC_PC_17214Medical Research Council MR/L021803/1Medical Research Council MR/L501529/1Medical Research Council MR/R024804/1Motor Neurone Disease Association ALCHALABI-DOBSON/APR14/829-791Motor Neurone Disease Association ALCHALABI-TALBOT/APR14/926-794Motor Neurone Disease Association MCLAUGHLIN/OCT15/957-799Motor Neurone Disease Association SHAW/APR18/864-791Motor Neurone Disease Association SHAW/NOV14/985-797Motor Neurone Disease Association SMITH/APR16/847-791NINDS NIH HHS R01 NS073873NINDS NIH HHS R56 NS073873Wellcome Trust
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.
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