Morahan et al. 2009MORAHAN JM, YU B, TRENT RJ & PAMPHLETT R. 2009. A genome-wide analysis of brain DNA methylation identifies new candidate genes for sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10: 418-429.
|
20 (10+ 10) |
Brain DNA |
sALS |
GWAS |
Altered methylation of genes related to cell death pathways in sALS patients |
Chestnut et al. 2011CHESTNUT BA, CHANG Q, PRICE A, LESUISSE C, WONG M & MARTIN LJ. 2011. Epigenetic Regulation of Motor Neuron Cell Death through DNA Methylation. J Neurosci 31: 16619-16636.
|
24 (12 + 12) (Human tissue) |
Mouse and Human CNS tissue |
sALS |
PCR |
Motor neuron shows changes in DNMT’s and 5mc in ALS patients |
Figueroa-Romero et al. 2012FIGUEROA-ROMERO C, HUR J, BENDER DE, DELANEY CE, CATALDO MD, SMITH AL, YUNG R, RUDEN DM, CALLAGHAN BC & FELDMAN EL. 2012. Identification of Epigenetically Altered Genes in Sporadic Amyotrophic Lateral Sclerosis. PLoS ONE 7: e52672.
|
23 (12+ 11) |
Human spinal cord tissue |
sALS |
ELISA; WGA |
Identification of sALS epigenetic regulatory mechanisms |
Wong et al. 2013WONG M, GERTZ B, CHESTNUT BA & MARTIN LJ. 2013. Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front Cell Neurosci 7: 1-16.
|
20 + 25 (mice); 4 (human CNS tissue) |
Mice and Human CNS tissue |
ALS |
Pyrosequencing |
mtDNA methylation patterns and DNMT3a levels are unnormal in skeletal muscle and spinal cord of presymptomatic ALS mice |
Xi et al. 2013XI Z ET AL. 2013. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92: 981-989.
|
177 (101+76) |
Blood |
C9ALS |
Bisulfite sequencing |
Higher degree of methylation is associated with a shorter disease duration in fALS |
Tremolizzo et al. 2014TREMOLIZZO L ET AL. 2014. Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset. Amyotroph Lateral Scler Front Degener 15: 98-105.
|
183 ( 96+ 87) |
Blood |
ALS |
Incorporation of [(3)H]dCTP following HpaII cut |
Increased DNA methylation as a marker in ALS dysfunction independently of age of onset |
Liu et al. 2014LIU EY, RUSS J, WU K, NEAL D, SUH E, MCNALLY AG, IRWIN DJ, VAN DEERLIN VM & LEE EB. 2014. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 128: 525-541.
|
38 (32+6); 35 (cell lines) |
Human tissue and peripheral DNA and cell lines |
C9ALS and FTD |
Bisulfite cloning and restriction enzyme-based methylation assays |
Epigenetic silence of mutant C9ORF72 it might be protective |
Russ et al. 2015RUSS J et al. 2015. Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129: 39-52.
|
137 (118 + 19) |
Brain samples and blood |
ALS and FTD |
qPCR |
Hypermethylation is associated with prolonged disease survival |
McMillan et al. 2015MCMILLAN CT, RUSS J, WOOD EM, IRWIN DJ, GROSSMAN M, MCCLUSKEY L, ELMAN L, VAN DEERLIN V & LEE EB. 2015. C9orf72 promoter hypermethylation is neuroprotective. Neurology 84: 1622-1630.
|
45 (20+ 25) |
Blood |
C9ALS |
Methylation-sensitive restriction enzyme DNA digestion coupled with quantitative PCR |
C9ORF72 promoter hypermethylation have neuroprotective properties |
Garton et al. 2017GARTON FC ET AL. 2017. Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort. Mol Genet Genomic Med 5: 418-428.
|
229 (118+111) |
Blood |
ALS |
Illumina HumanMethylation 450 array |
Investigations on SOD1 and TARDBP did not suggest that DNA methylation signatures from blood are helpful in assessing functionality of these rare single-nucleotide variants. |
Zhang et al. 2017ZHANG M, TARTAGLIA MC, MORENO D, SATO C, MCKEEVER P, WEICHERT A, KEITH J, ROBERTSON J, ZINMAN L & ROGAEVA E. 2017. DNA methylation age-acceleration is associated with disease duration and age at onset in C9orf72 patients. Acta Neuropathol 134: 271-279.
|
46 patients |
Blood and CNS tissues |
C9ALS and FTD |
Infinium HumanMethylation 450k BeadChip |
DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset. |
Hamzeiy et al. 2018HAMZEIY H ET AL. 2018. Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2. Neurodegener Dis 18: 38-48.
|
550 (405+145) |
Blood |
sALS; fALS; C9ALS; SCA1 and 2; HD; FRDA; DM1 |
ELISA and direct bisulfite sequencing |
Significant elevation in global 5-mC levels of about 2-7% on average for sALS and various forms of fALS |
Stoccoro et al. 2018STOCCORO A, MOSCA L, CARNICELLI V, CAVALLARI U, LUNETTA C, MAROCCHI A, MIGLIORE L & COPPEDÈ F. 2018. Mitochondrial DNA copy number and D-loop region methylation in carriers of amyotrophic lateral sclerosis gene mutations. Epigenomics 10: 1431-1443.
|
144 (54 + 60) |
Blood |
ALS |
MS-HRM; qPCR |
Demethylation of d-loop it might be a compensatory mechanism for mtDNA upregulation in carriers of SOD1 |
Coppedè et al. 2018COPPEDÈ F, STOCCORO A, MOSCA L, GALLO R, TARLARINI C, LUNETTA C, MAROCCHI A, MIGLIORE L & PENCO S. 2018. Increase in DNA methylation in patients with amyotrophic lateral sclerosis carriers of not fully penetrant SOD1 mutations. Amyotroph Lateral Scler Front Degener 19: 93-101.
|
35 (17+ 18) |
Blood |
fALS |
ELISA ; MS-HRM |
DNA metylation levels it might contribute to ALS phenotype of not fully penetrant SOD1 mutations |
Tarr et al. 2019TARR IS ET AL. 2019. Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression. Sci Rep 9: 1-17.
|
4 (3+ 1) |
Blood |
fALS |
EpiTYPER |
High methylation age is a sigature of ALS in older patients |
Nabais et al. 2020NABAIS MF ET AL. 2020. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis. NPJ genomic medicine 5: 1-9.
|
1.395 (782 + 613) |
Blood |
ALS |
Illumina Infinium HumanMethylation450 Beadchip and MOMENT |
Identification of 1 DMP between ALS cases and controls, which is annotated to CXXC5 on chromosome 5 |
Kim et al. 2020KIM BW, JEONG YE, WONG M & MARTIN LJ. 2020. DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations. Acta Neuropathol Commun 8: 1-26.
|
49 (34+ 15) |
Human post mortem CNS tissue |
ALS |
Pyrosequencing |
Vulnerable neurons in human ALS accumulate DNA damage and activate and mobilize response effectors |
Jackson et al. 2020JACKSON JL ET AL. 2020. Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers. Mol Neurodegener 15: 1-11.
|
195 (108+87) |
Blood |
C9ALS |
Quantitative methylation-sensitive restriction enzyme-based assays, digital molecular barcoding, quantitative real-time PCR, and Southern blotting |
Elevated methylation levels, reduced expression levels and unstable expansions in C9ORF72 carries |
Zhang et al. 2020ZHANG M, MCKEEVER PM, XI Z, MORENO D, SATO C, BERGSMA T, MCGOLDRICK P, KEITH J, ROBERTSON J, ZINMAN L & ROGAEVA E. 2020. DNA methylation age acceleration is associated with ALS age of onset and survival. Acta Neuropathol 139: 943-946.
|
267 (249+ 18) |
Blood and CNS tissues |
ALS |
GWAS |
DNAm-age acceleration as biomarker |
Appleby-Mallinder et al. 2021APPLEBY-MALLINDER C, SCHABER E, KIRBY J, SHAW PJ, COOPER-KNOCK J, HEATH PR & HIGHLEY JR. 2021. TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 47: 61-72.
|
124 (95+29) |
Human post mortem spinal cord, motor cortex and anterior frontal cortex |
sALS and C9ALS |
Immunohistochemistry; Methylation EPIC array |
DNA methylation contributes to LMN pathology |
Nabais et al. 2021NABAIS MF ET AL. 2021. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders. Genome Biol 22: 1-30.
|
9.894 (5.551 + 4.343) |
Blood |
ALS; PD; AD; SCZ1; SCZ2; RA |
MOMENT |
Shared differentially methylated positions in different neurodegenerative disorders |
Zhang et al. 2021ZHANG M, XI Z, ATIENZAR SS, CHIA R, MORENO D, SATO C, HAGHIGHI MM, TRAYNOR BJ, ZINMAN L & ROGAEVA E. 2021. Combined epigenetic / genetic study identified an ALS age of onset modifier. Acta Neuropathol Commun 9(1): 1-9.
|
249 |
Blood |
ALS |
Methylation EPIC BeadChip |
16kb locus tagged by rs4970944 can be a modifer of ALS age of onset (each A-allele delays onset by 1.6 years) |
Cai et al. 2022CAI Z, JIA X, LIU M, YANG X & CUI L. 2022. Epigenome-wide DNA methylation study of whole blood in patients with sporadic amyotrophic lateral sclerosis. Chin Med J (Engl) 135: 1466-1473.
|
64(32+32) |
Blood |
sALS |
Infinium Methylation EPIC BeadChip |
34 DMPs from 13 genes and 12 DMRs from 12 genes. Genes ELOVL2 and ARID1B was positively associated with the age of onset and disease duration, respectively. |
Hop et al. 2022HOP PJ ET AL. 2022. Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways. Sci Transl Med 14: eabj0264.
|
10.462 (7.344+ 3.118) |
Blood |
ALS |
EWAS |
45 DMPs from 42 genes enriched for pathways related to metabolism, cholesterol biosynthesis and immunity pathways |