SOD1-ALS-Browser: a web-utility for investigating the clinical phenotype in SOD1 amyotrophic lateral sclerosis

Abstract

Objective

Variants in the superoxide dismutase (SOD1) gene are among the most common genetic causes of amyotrophic lateral sclerosis. Reflecting the wide spectrum of putatively deleterious variants that have been reported to date, it has become clear that SOD1-linked ALS presents a highly variable age at symptom onset and disease duration.

Methods

Here we describe an open access web tool for comparative phenotype analysis in ALS: https://sod1-als-browser.rosalind.kcl.ac.uk/. The tool contains a built-in dataset of clinical information from 1383 people with ALS harboring a SOD1 variant resulting in one of 162 unique amino acid sequence alterations and from a non-SOD1 comparator ALS cohort of 13,469 individuals. We present two examples of analyses possible with this tool, testing how the ALS phenotype relates to SOD1 variants that alter amino acid residue hydrophobicity and to distinct variants at the 94^th residue of SOD1, where six are sampled.

Results and conclusions

The tool provides immediate access to the datasets and enables bespoke analysis of phenotypic trends associated with different protein variants, including the option for users to upload their own datasets for integration with the server data. The tool can be used to study SOD1-ALS and provides an analytical framework to study the differences between other user-uploaded ALS groups and our large reference database of SOD1 and non-SOD1 ALS. The tool is designed to be useful for clinicians and researchers, including those without programming expertise, and is highly flexible in the analyses that can be conducted.

Keywords:

• Kaplan-Meier
• cox proportional-hazards
• SOD1
• amyotrophic lateral sclerosis
• online tool

Acknowledgments

Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. Part of the samples were obtained from The Project MinE and STRENGTH consortia, and MND centers internationally. We would like to thank the members of these consortia and our clinical collaborators for their contribution: Philip van Damme, Philippe Corcia, Philippe Couratier, Patrick Vourc”h, Orla Hardiman, Russell McLaughin, Marc Gotkine, Vivian Drory, Nicola Ticozzi, Vincenzo Silani, Jan H Veldink, Leonard H van den Berg, Mamede de Carvalho, Jesus S Mora Pardina, Monica Povedano, Peter Andersen, Markus Weber, Nazli A Başak, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, John E Landers, Jonathan D Glass, Clifton L Dalgard, Nailah Siddique, Teepu Siddique, Kelly L Williams, Ian P Blair, Jennifer Jockel-Balsarotti, Lyndal Henden, Garth A Nicholson, Timothy Miller, Diane McKenna-Yasek, Robert H Brown, William Camu, Zorica Stevic, Lu Tang, Dong-sheng Fan. We thank people with MND and their families for their participation in this project. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Center for Integrated Genomic Medical Research, University of Manchester. The authors acknowledge use of the research computing facility at King”s College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health and Care Research (NIHR) Biomedical Research Centers at South London and Maudsley and Guy”s and St. Thomas” NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy”s and St. Thomas” Charity (TR130505). The authors also acknowledge the use of the CREATE research computing facility at King”s College London (38). We also acknowledge Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (United Kingdom), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust.

Declaration of interest

TS is employed by AstraZeneca. The other authors report no conflict of interest.

Data availability statement

All data associated with this manuscript can be accessed from the web-utility: https://sod1-als-browser.rosalind.kcl.ac.uk/.

Additional information

Funding

AAK is funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609.doi: 10.52546/pc.gr.150909), The Motor Neurone Disease Association (MNDA) Fellowship (Al Khleifat/Oct21/975-799), The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Centre. This project was also funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND–http://www.neurodegenerationresearch.eu/ [United Kingdom, Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)]. AAC is a NIHR Senior Investigator. AAC receives salary support from the National Institute for Health and Care Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 772376–EScORIAL. This study represents independent research part funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. AI is funded by South London and Maudsley NHS Foundation Trust, MND Scotland, Motor Neurone Disease Association, National Institute for Health and Care Research, Spastic Paraplegia Foundation, Rosetrees Trust, Darby Rimmer MND Foundation, the Medical Research Council (UKRI) and Alzheimer’s Research UK. MK is supported by Darby Rimmer MND Foundation and Spastic Paraplegia Foundation. GH is supported by King's College London DRIVE-Health Centre for Doctoral Training, the Medical Research Council and the Perron Institute for Neurological and Translational Science.