Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression

• Published in: Scientific reports 2019-06, Vol.9 (1), p.8254-8254, Article 8254
• Main Authors: Tarr, Ingrid S., McCann, Emily P., Benyamin, Beben, Peters, Timothy J., Twine, Natalie A., Zhang, Katharine Y., Zhao, Qiongyi, Zhang, Zong-Hong, Rowe, Dominic B., Nicholson, Garth A., Bauer, Denis, Clark, Susan J., Blair, Ian P., Williams, Kelly L.
• Format: Article
• Language: English
• Subjects: 38; 38/91; 45; 631/1647/2017; 631/1647/2210/2213; 631/208/176/1988; 631/208/199; 692/617/375/1917/1285; Adult; Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Australia - epidemiology; C9orf72 Protein - genetics; Cell Cycle Proteins - genetics; Diseases in Twins; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic; Epigenetics; Female; Gene expression; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Genetic variability; Humanities and Social Sciences; Humans; Immune response; Male; Middle Aged; Motor neurons; multidisciplinary; Neurodegenerative diseases; Phenotype; Phenotypes; Protein folding; Receptor activity modifying proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Superoxide dismutase; Triplets - genetics; Twins; Twins, Monozygotic - genetics; Whole Exome Sequencing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-44765-4

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. 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 = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1 . Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46 , showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF , DPP6 , RAMP3 , and CCS , 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.