Harnessing Transcriptomic Signals for Amyotrophic Lateral Sclerosis to Identify Novel Drugs and Enhance Risk Prediction

Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics. Methods Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival. Results SNP-based fine-mapping, TWAS and PWAS identified 117 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified five drugs significantly enriched for interactions with ALS associated genes, with directional analyses highlighting α-glucosidase inhibitors may exacerbate ALS pathology. Additionally, drug class enrichment analysis showed calcium channel blockers may reduce ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk ( R 2 = 4%; p -value = 2.1×10−21). Conclusions Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk. ### Competing Interest Statement OP provides consultancy services for UCB pharma company. AAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals. The other authors declare no competing interests. ### Funding Statement OP is supported by a Sir Henry Wellcome Postdoctoral Fellowship [222811/Z/21/Z]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AI is funded by South London and Maudsley NHS Foundation Trust, MND Scotland, Motor Neurone Disease Association, National Institute for Health Research, Spastic Paraplegia Foundation, Rosetrees Trust and Darby Rimmer MND Foundation. Funding for open access charge: UKRI. AAC is an NIHR Senior Investigator (NIHR202421). This is in part an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - [www.jpnd.eu][1] (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1)). This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. OP, AI and AAC obtained additional financial support for this study from the Turing Institute. JK was supported by the Polish National Science Centre [2020/37/B/NZ2/03268]. AAK is funded by ALS Association Milton Safenowitz Research Fellowship (grant number22-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. JMR is supported by Alzheimer's Research UK and the Alan Turing Institute/Engineering and Physical Sciences Research Council (EP/N510129/1). DJL is supported by Alzheimer's Research UK, National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) South West Peninsula, National Health and Medical Research Council (NHMRC), National Institute on Aging/National Institutes of Health (RF1AG055654), and the Alan Turing Institute/Engineering and Physical Sciences Research Council (EP/N510129/1). AJ was funded by the MND Association grant number Jones/Oct15/958-799. This work was facilitated by the NEUROHACK 2022 hackathon, organized by the Deep Dementia Phenotyping (DEMON) Network, with additional financial support from the Alan Turing Institute, Alzheimer's Research UK, the Motor Neurone Disease Association, (MNDA) and LifeArc. This research was funded in whole or in part by the Wellcome Trust [222811/Z/21/Z]. For the purpose of open access, the author has applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data used is publicly available except individual-level data from the KCL BrainBank. Post-mortem tissue samples from the KCL BrainBank were collected under the ethical approval of the MRC London Neurodegenerative Diseases Brain Bank and under the regulations of the Human Tissue Act UK 2014. All post-mortem tissue was donated to the MRC London Neurodegenerative Diseases Brain Bank under standard ethical and Human Tissue Act procedures, with informed consent provided by the next of kin. Data generated from this material were anonymized and analysed on a high-performance computing cloud () with data protection protocols in accordance with Department of Health Policy (UK) and the security standards set by the National Data Guardian. Ethical approval to process and analyse post-mortem samples stored at King's College London was provided by a local ethics committee at the Institute of Psychiatry, Psychology & Neuroscience, King's College London, and the MRC London Neurodegenerative Diseases Brain Bank. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][2]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: http://www.jpnd.eu [2]: http://ClinicalTrials.gov