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ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n\u2009=\u20093 pairs) and triplets (n\u2009=\u20091 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to <jats:italic>C9orf72<\/jats:italic> and <jats:italic>SOD1<\/jats:italic>. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins\/triplets and control twins (n\u2009=\u20092 pairs), implicated genes with consistent longitudinal differential DNA methylation and\/or gene expression. Two identified genes, <jats:italic>RAD9B<\/jats:italic> and <jats:italic>C8orf46<\/jats:italic>, showed significant differential methylation in an extended cohort of &gt;1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated <jats:italic>CCNF<\/jats:italic>, <jats:italic>DPP6<\/jats:italic>, <jats:italic>RAMP3<\/jats:italic>, and <jats:italic>CCS<\/jats:italic>, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.<\/jats:p>","DOI":"10.1038\/s41598-019-44765-4","type":"journal-article","created":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T10:07:20Z","timestamp":1559642840000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4847-2838","authenticated-orcid":false,"given":"Ingrid S.","family":"Tarr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8200-3525","authenticated-orcid":false,"given":"Emily P.","family":"McCann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5608-2293","authenticated-orcid":false,"given":"Beben","family":"Benyamin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3690-5293","authenticated-orcid":false,"given":"Timothy J.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2051-8275","authenticated-orcid":false,"given":"Natalie A.","family":"Twine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine Y.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6341-0416","authenticated-orcid":false,"given":"Qiongyi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong-Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0912-2146","authenticated-orcid":false,"given":"Dominic B.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garth A.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8033-9810","authenticated-orcid":false,"given":"Denis","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5925-5030","authenticated-orcid":false,"given":"Susan J.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3083-0075","authenticated-orcid":false,"given":"Ian P.","family":"Blair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6319-9473","authenticated-orcid":false,"given":"Kelly L.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"key":"44765_CR1","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nrneurol.2014.184","volume":"10","author":"B Swinnen","year":"2014","unstructured":"Swinnen, B. & Robberecht, W. 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