Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Ahmad Al Khleifat¹, Alfredo Iacoangeli^{1

2}, Joke J F A van Vugt³, Harry Bowles¹, Matthieu Moisse⁴, Ramona A J Zwamborn³, Rick A A van der Spek³, Aleksey Shatunov¹, Johnathan Cooper-Knock⁵, Simon Topp¹, Ross Byrne⁶, Cinzia Gellera⁷, Victoria López⁷, Ashley R Jones¹, Sarah Opie-Martin¹, Atay Vural⁸, Yolanda Campos⁹, Wouter van Rheenen³, Brendan Kenna³, Kristel R Van Eijk³, Kevin Kenna³, Markus Weber¹⁰, Bradley Smith¹, Isabella Fogh¹, Vincenzo Silani⁷, Karen E Morrison¹¹, Richard Dobson^{2

12}, Michael A van Es³, Russell L McLaughlin⁶, Patrick Vourc'h¹³, Adriano Chio^{14

15}, Philippe Corcia^{13

16}, Mamede de Carvalho¹⁷, Marc Gotkine¹⁸, Monica P Panades¹⁹, Jesus S Mora²⁰, Pamela J Shaw⁵, John E Landers²¹, Jonathan D Glass²², Christopher E Shaw^{1

23}, Nazli Basak⁸, Orla Hardiman^{24

25}, Wim Robberecht^{4

26}, Philip Van Damme^{4

26}, Leonard H van den Berg³, Jan H Veldink³, Ammar Al-Chalabi^{27

28}

Affiliations

¹ King's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
² Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³ Department of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
⁴ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
⁵ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
⁶ Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
⁷ 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, Milano, Italy.
⁸ Koc University, School of Medicine, Translational Medicine Research Center- NDAL, Istanbul, Turkey.
⁹ Mitochondrial pathology Unit, Instituto de Salud Carlos III, Madrid, Spain.
¹⁰ Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹¹ Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
¹² Institute of Health Informatics, University College London, London, UK.
¹³ Centre SLA, CHRU de Tours, Tours, France.
¹⁴ Rita Levi Montalcini, Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
¹⁵ Azienda Ospedaliera Citta della Salute e della Scienza, Torino, Italy.
¹⁶ Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France.
¹⁷ Physiology Institute, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal.
¹⁸ Hadassah University Hospital, Jerusalem, Israel.
¹⁹ Neurology Department, Hospital Universitari de Bellvitge, Barcelona, Spain.
²⁰ Hospital San Rafael, Madrid, Spain.
²¹ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
²² Department of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA.
²³ King's College Hospital, Denmark Hill, London, UK.
²⁴ Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland.
²⁵ Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland.
²⁶ Neurology Department, University Hospitals Leuven, Leuven, Belgium.
²⁷ King'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.
²⁸ King's College Hospital, Denmark Hill, London, UK. ammar.al-chalabi@kcl.ac.uk.

PMID: 35091648
PMCID: PMC8799638
DOI: 10.1038/s41525-021-00267-9

Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Ahmad Al Khleifat et al. NPJ Genom Med. 2022.

. 2022 Jan 28;7(1):8.

doi: 10.1038/s41525-021-00267-9.

Authors

Affiliations

¹ King's College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, De Crespigny Park, London, UK.
² Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³ Department of Neurology, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
⁴ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
⁵ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
⁶ Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
⁷ 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, Milano, Italy.
⁸ Koc University, School of Medicine, Translational Medicine Research Center- NDAL, Istanbul, Turkey.
⁹ Mitochondrial pathology Unit, Instituto de Salud Carlos III, Madrid, Spain.
¹⁰ Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹¹ Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
¹² Institute of Health Informatics, University College London, London, UK.
¹³ Centre SLA, CHRU de Tours, Tours, France.
¹⁴ Rita Levi Montalcini, Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
¹⁵ Azienda Ospedaliera Citta della Salute e della Scienza, Torino, Italy.
¹⁶ Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France.
¹⁷ Physiology Institute, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal.
¹⁸ Hadassah University Hospital, Jerusalem, Israel.
¹⁹ Neurology Department, Hospital Universitari de Bellvitge, Barcelona, Spain.
²⁰ Hospital San Rafael, Madrid, Spain.
²¹ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
²² Department of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA.
²³ King's College Hospital, Denmark Hill, London, UK.
²⁴ Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland.
²⁵ Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland.
²⁶ Neurology Department, University Hospitals Leuven, Leuven, Belgium.
²⁷ King'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.
²⁸ King's College Hospital, Denmark Hill, London, UK. ammar.al-chalabi@kcl.ac.uk.

PMID: 35091648
PMCID: PMC8799638
DOI: 10.1038/s41525-021-00267-9

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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Conflict of interest statement

A.A.C. is a consultant for Mitsubishi-Tanabe Pharma, GSK, and Chronos Therapeutics, and chief investigator for clinical trials for Cytokinetics and OrionPharma. J.H.V. is a consultant for Biogen. L.H.V.D.B. reports grants from Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community’s Health Seventh Framework Programme (grant agreement no. 259867 (EuroMOTOR)), grants from The Netherlands Organization for Health Research and Development)the STRENGTH project, funded through the EU Joint Programme – Neurodegenerative Disease Research, JPND), during the conduct of the study; personal fees from Calico, personal fees from Cytokinetics, grants and personal fees from Takeda, non-financial support from Orion, non-financial support from Orphazyme, outside the submitted work. CES reports grants from Avexis, grants from Eli Lilly, grants from Chronos Therapeutics, grants from Vertex Pharmaceuticals, during the conduct of the study; grants from QurAlis, grants from Chronos Therapeutics, grants from Biogen, outside the submitted work. A.A.K., O.H., M.P.P., J.S.M., P.J.S., J.E.L., C.E.S., N.B., O.H., W.R., P.V.D., N.B., K.K., B.K., H.B., and L.H.V.B. declare no competing interests.

References

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Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Affiliations

Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous