{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T23:36:31Z","timestamp":1778110591603,"version":"3.51.4"},"posted":{"date-parts":[[2023,1,18]]},"group-title":"Genetic and Genomic Medicine","reference-count":49,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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 \u03b1-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 (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 4%;\n                    <jats:italic>p<\/jats:italic>\n                    -value = 2.1\u00d710\n                    <jats:sup>\u221221<\/jats:sup>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.18.23284589","type":"posted-content","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:50:13Z","timestamp":1674089413000},"source":"Crossref","is-referenced-by-count":8,"title":["Harnessing Transcriptomic Signals for Amyotrophic Lateral Sclerosis to Identify Novel Drugs and Enhance Risk Prediction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5680-3281","authenticated-orcid":false,"given":"Oliver","family":"Pain","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad Al","family":"Khleifat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devika","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dzmitry","family":"Hramyka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hajer","family":"Karoui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u0119drzej","family":"Kubica","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Llewellyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice M.","family":"Ranson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Iacoangeli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-7712","authenticated-orcid":false,"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023012613100818000_2023.01.18.23284589v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"2023012613100818000_2023.01.18.23284589v2.2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.207464"},{"issue":"2","key":"2023012613100818000_2023.01.18.23284589v2.3","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrneurol.2016.182","article-title":"Gene discovery in amyotrophic lateral sclerosis: implications for clinical management","volume":"13","year":"2017","journal-title":"Nature Reviews Neurology"},{"issue":"7\u20138","key":"2023012613100818000_2023.01.18.23284589v2.4","first-page":"485","article-title":"Focus on the heterogeneity of amyotrophic lateral sclerosis","volume":"21","year":"2020","journal-title":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration"},{"key":"2023012613100818000_2023.01.18.23284589v2.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1603471"},{"key":"2023012613100818000_2023.01.18.23284589v2.6","doi-asserted-by":"crossref","unstructured":"Choi, S. W. , Mak, T. S.-H. , & O\u2019Reilly, P. F. (2020). Tutorial: a guide to performing polygenic risk score analyses. Nature Protocols, 1\u201314.","DOI":"10.1038\/s41596-020-0353-1"},{"issue":"1","key":"2023012613100818000_2023.01.18.23284589v2.7","first-page":"25","article-title":"Edaravone (Radicava): a novel neuroprotective agent for the treatment of amyotrophic lateral sclerosis","volume":"43","year":"2018","journal-title":"Pharmacy and Therapeutics"},{"key":"2023012613100818000_2023.01.18.23284589v2.8","doi-asserted-by":"crossref","unstructured":"Dall\u2019Aglio, L. , Lewis, C. M. , & Pain, O. (2020). Delineating the Genetic Component of Gene Expression in Major Depression. Biological Psychiatry. https:\/\/doi.org\/10.1016\/j.biopsych.2020.09.010","DOI":"10.1016\/j.biopsych.2020.09.010"},{"key":"2023012613100818000_2023.01.18.23284589v2.9","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00087.2001"},{"key":"2023012613100818000_2023.01.18.23284589v2.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"2023012613100818000_2023.01.18.23284589v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"2023012613100818000_2023.01.18.23284589v2.12","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000285080.70324.27"},{"key":"2023012613100818000_2023.01.18.23284589v2.13","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4000"},{"issue":"14","key":"2023012613100818000_2023.01.18.23284589v2.14","first-page":"2515","article-title":"Drug Targetor: a web interface to investigate the human druggome for over 500 phenotypes","volume":"35","year":"2018","journal-title":"Bioinformatics"},{"issue":"5","key":"2023012613100818000_2023.01.18.23284589v2.15","doi-asserted-by":"crossref","first-page":"e1004383","DOI":"10.1371\/journal.pgen.1004383","article-title":"Bayesian test for colocalisation between pairs of genetic association studies using summary statistics","volume":"10","year":"2014","journal-title":"PLoS Genetics"},{"key":"2023012613100818000_2023.01.18.23284589v2.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1262110"},{"key":"2023012613100818000_2023.01.18.23284589v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3506"},{"key":"2023012613100818000_2023.01.18.23284589v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0092-1"},{"key":"2023012613100818000_2023.01.18.23284589v2.19","doi-asserted-by":"crossref","unstructured":"Heo, Y.-A. (2022). Sodium Phenylbutyrate and Ursodoxicoltaurine: First Approval. CNS Drugs, 1\u20137.","DOI":"10.1007\/s40263-022-00945-x"},{"key":"2023012613100818000_2023.01.18.23284589v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0364-4"},{"issue":"4","key":"2023012613100818000_2023.01.18.23284589v2.21","doi-asserted-by":"crossref","first-page":"fcab236","DOI":"10.1093\/braincomms\/fcab236","article-title":"SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed","volume":"3","year":"2021","journal-title":"Brain Communications"},{"key":"2023012613100818000_2023.01.18.23284589v2.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616332114"},{"key":"2023012613100818000_2023.01.18.23284589v2.23","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-006-0195-y"},{"issue":"1","key":"2023012613100818000_2023.01.18.23284589v2.24","first-page":"1","article-title":"A HML6 endogenous retrovirus on chromosome 3 is upregulated in amyotrophic lateral sclerosis motor cortex","volume":"11","year":"2021","journal-title":"Scientific Reports"},{"issue":"9","key":"2023012613100818000_2023.01.18.23284589v2.25","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1001\/jamaneurol.2014.1184","article-title":"Genome-wide analysis of the heritability of amyotrophic lateral sclerosis","volume":"71","year":"2014","journal-title":"JAMA Neurology"},{"issue":"8","key":"2023012613100818000_2023.01.18.23284589v2.26","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1001\/jamaneurol.2015.0910","article-title":"Diabetes mellitus, obesity, and diagnosis of amyotrophic lateral sclerosis: a population-based study","volume":"72","year":"2015","journal-title":"JAMA Neurology"},{"issue":"13","key":"2023012613100818000_2023.01.18.23284589v2.27","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1517\/14656566.7.13.1825","article-title":"Sertindole: efficacy and safety in schizophrenia","volume":"7","year":"2006","journal-title":"Expert Opinion on Pharmacotherapy"},{"key":"2023012613100818000_2023.01.18.23284589v2.28","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3936"},{"issue":"8","key":"2023012613100818000_2023.01.18.23284589v2.29","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1001\/jamaneurol.2014.4049","article-title":"Heritability of amyotrophic lateral sclerosis: insights from disparate numbers","volume":"72","year":"2015","journal-title":"JAMA Neurology"},{"key":"2023012613100818000_2023.01.18.23284589v2.30","doi-asserted-by":"crossref","unstructured":"Mehta, P. R. , Iacoangeli, A. , Opie-Martin, S. , van Vugt, J. J. F. A. , al Khleifat, A. , Bredin, A. , Ossher, L. , Andersen, P. M. , Hardiman, O. , & Mehta, A. R. (2022). The impact of age on genetic testing decisions in amyotrophic lateral sclerosis. Brain.","DOI":"10.1093\/brain\/awac279"},{"key":"2023012613100818000_2023.01.18.23284589v2.31","doi-asserted-by":"crossref","unstructured":"Miller, R. G. , Mitchell, J. D. , & Moore, D. H. (2012). Riluzole for amyotrophic lateral sclerosis (ALS)\/motor neuron disease (MND). Cochrane Database of Systematic Reviews, 3.","DOI":"10.1002\/14651858.CD001447.pub3"},{"key":"2023012613100818000_2023.01.18.23284589v2.32","doi-asserted-by":"crossref","unstructured":"Pain, O. , Glanville, K. P. , Hagenaars, S. , Selzam, S. , F\u00fcrtjes, A. , Coleman, J. R. I. , Rimfeld, K. , Breen, G. , Folkersen, L. , & Lewis, C. M. (2021). Imputed Gene Expression Risk Scores: A Functionally Informed Component of Polygenic Risk. Human Molecular Genetics, ddab053. https:\/\/doi.org\/10.1093\/hmg\/ddab053","DOI":"10.1101\/2020.12.01.369462"},{"issue":"4","key":"2023012613100818000_2023.01.18.23284589v2.33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.biopsych.2019.04.034","article-title":"Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics","volume":"86","year":"2019","journal-title":"Biological Psychiatry"},{"key":"2023012613100818000_2023.01.18.23284589v2.34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2023012613100818000_2023.01.18.23284589v2.35","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.RA119000119"},{"issue":"3","key":"2023012613100818000_2023.01.18.23284589v2.36","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ajhg.2022.01.005","article-title":"Leveraging gene co-regulation to identify gene sets enriched for disease heritability","volume":"109","year":"2022","journal-title":"The American Journal of Human Genetics"},{"key":"2023012613100818000_2023.01.18.23284589v2.37","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4618"},{"key":"2023012613100818000_2023.01.18.23284589v2.38","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(17)31287-4"},{"key":"2023012613100818000_2023.01.18.23284589v2.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0198874"},{"key":"2023012613100818000_2023.01.18.23284589v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00973-1"},{"issue":"2","key":"2023012613100818000_2023.01.18.23284589v2.41","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1001\/jamaneurol.2020.4300","article-title":"Effect of ezogabine on cortical and spinal motor neuron excitability in amyotrophic lateral sclerosis: a randomized clinical trial","volume":"78","year":"2021","journal-title":"JAMA Neurology"},{"key":"2023012613100818000_2023.01.18.23284589v2.42","doi-asserted-by":"crossref","unstructured":"Wang, G. , Sarkar, A. , Carbonetto, P. , & Stephens, M. (2020). A simple new approach to variable selection in regression, with application to genetic fine-mapping. BioRxiv, 501114.","DOI":"10.1111\/rssb.12388"},{"key":"2023012613100818000_2023.01.18.23284589v2.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00773-z"},{"issue":"1","key":"2023012613100818000_2023.01.18.23284589v2.44","first-page":"1","article-title":"Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study","volume":"17","year":"2022","journal-title":"Orphanet Journal of Rare Diseases"},{"key":"2023012613100818000_2023.01.18.23284589v2.45","doi-asserted-by":"crossref","unstructured":"Yao, D. W. , O\u2019Connor, L. J. , Price, A. L. , & Gusev, A. (2020). Quantifying genetic effects on disease mediated by assayed gene expression levels. Nature Genetics, 1\u20138.","DOI":"10.1101\/730549"},{"issue":"1","key":"2023012613100818000_2023.01.18.23284589v2.46","first-page":"1","article-title":"Association between type 2 diabetes and amyotrophic lateral sclerosis","volume":"12","year":"2022","journal-title":"Scientific Reports"},{"key":"2023012613100818000_2023.01.18.23284589v2.47","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3538"},{"key":"2023012613100818000_2023.01.18.23284589v2.48","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2057-x"},{"key":"2023012613100818000_2023.01.18.23284589v2.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2005748117"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.01.18.23284589","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:25:28Z","timestamp":1768505128000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.01.18.23284589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,18]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1101\/2023.01.18.23284589","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.heliyon.2024.e35342","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,1,18]]},"subtype":"preprint"}}