{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T11:55:48Z","timestamp":1793015748579,"version":"4.5.0"},"reference-count":132,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for N. Ireland, Northern Ireland Public Health Agency (HSC R&amp;D) &amp; Ulster University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide data have offered insight into the biological processes and pathways of complex diseases and can suggest new hypotheses regarding causal mechanisms. Our aim in this study was to identify and explore biological pathways and other gene sets having genomic association to ALS. Two cohorts of genomic data from the dbGaP repository were combined: (a) the largest available ALS individual-level genotype dataset (N = 12,319), and (b) a similarly sized control cohort (N = 13,210). Following comprehensive quality control pipelines, imputation and meta-analysis, we assembled a large European descent ALS-control cohort of 9244 ALS cases and 12,795 healthy controls represented by genetic variants of 19,242 genes. Multi-marker analysis of genomic annotation (MAGMA) gene-set analysis was applied to an extensive collection of 31,454 gene sets from the molecular signatures database (MSigDB). Statistically significant associations were observed for gene sets related to immune response, apoptosis, lipid metabolism, neuron differentiation, muscle cell function, synaptic plasticity and development. We also report novel interactions between gene sets, suggestive of mechanistic overlaps. A manual meta-categorization and enrichment mapping approach is used to explore the overlap of gene membership between significant gene sets, revealing a number of shared mechanisms.<\/jats:p>","DOI":"10.3390\/ijms24044021","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T01:59:24Z","timestamp":1676599164000},"page":"4021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5351-0130","authenticated-orcid":false,"given":"Christina","family":"Vasilopoulou","sequence":"first","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"McDaid-McCloskey","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1008-598X","authenticated-orcid":false,"given":"Gavin","family":"McCluskey","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6510-5426","authenticated-orcid":false,"given":"Stephanie","family":"Duguez","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Morris","sequence":"additional","affiliation":[{"name":"Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2239-9094","authenticated-orcid":false,"given":"William","family":"Duddy","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.chest.2018.06.035","article-title":"Respiratory Failure in Amyotrophic Lateral Sclerosis","volume":"155","author":"Niedermeyer","year":"2019","journal-title":"Chest"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1159\/000351153","article-title":"Global Epidemiology of Amyotrophic Lateral Sclerosis: A Systematic Review of the Published Literature","volume":"41","author":"Logroscino","year":"2013","journal-title":"Neuroepidemiology"},{"key":"ref_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","author":"Veldink","year":"2017","journal-title":"Nat. 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