{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:46:40Z","timestamp":1793249200826,"version":"4.5.0"},"reference-count":74,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"633","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,2,23]]},"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation\u2013based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.<\/jats:p>","DOI":"10.1126\/scitranslmed.abj0264","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T13:56:10Z","timestamp":1645624570000},"source":"Crossref","is-referenced-by-count":103,"title":["Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9007-7436","authenticated-orcid":true,"given":"Paul J.","family":"Hop","sequence":"first","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht 3584 CX, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3952-5042","authenticated-orcid":true,"given":"Ramona A.J.","family":"Zwamborn","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht 3584 CX, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6840-072X","authenticated-orcid":true,"given":"Eilis","family":"Hannon","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter EX1 2LU, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8238-0080","authenticated-orcid":true,"given":"Gemma L.","family":"Shireby","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter EX1 2LU, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9545-5889","authenticated-orcid":true,"given":"Marta F.","family":"Nabais","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter EX1 2LU, UK."},{"name":"Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD4072, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2222-4577","authenticated-orcid":true,"given":"Emma M.","family":"Walker","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter EX1 2LU, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5860-1533","authenticated-orcid":true,"given":"Wouter","family":"van Rheenen","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht 3584 CX, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-4004","authenticated-orcid":true,"given":"Joke J.F.A.","family":"van Vugt","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht 3584 CX, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelot M.","family":"Dekker","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht 3584 CX, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk-Jan","family":"Westeneng","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center 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