Dataset Information

Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis.

ABSTRACT: We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case-control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case-control status in the Netherlands sample (area under the curve, AUC?=?0.65, CI95%?=?[0.62-0.68], p?=?8.3?×?10-22). The maximum AUC achieved was 0.69 (CI95%?=?[0.66-0.71], p?=?4.3?×?10-34) when cell-type proportion was included in the predictor.

SUBMITTER: Nabais MF

PROVIDER: S-EPMC7046630 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis.

Nabais Marta F MF Lin Tian T Benyamin Beben B Williams Kelly L KL Garton Fleur C FC Vinkhuyzen Anna A E AAE Zhang Futao F Vallerga Costanza L CL Restuadi Restuadi R Freydenzon Anna A Zwamborn Ramona A J RAJ Hop Paul J PJ Robinson Matthew R MR Gratten Jacob J Visscher Peter M PM Hannon Eilis E Mill Jonathan J Brown Matthew A MA Laing Nigel G NG Mather Karen A KA Sachdev Perminder S PS Ngo Shyuan T ST Steyn Frederik J FJ Wallace Leanne L Henders Anjali K AK Needham Merrilee M Veldink Jan H JH Mathers Susan S Nicholson Garth G Rowe Dominic B DB Henderson Robert D RD McCombe Pamela A PA Pamphlett Roger R Yang Jian J Blair Ian P IP McRae Allan F AF Wray Naomi R NR

NPJ genomic medicine 20200227

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case-control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown i ...[more]

PMID: 32140259

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Project description:BackgroundMitochondrial dysregulation and aberrant epigenetic mechanisms have been frequently reported in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and several researchers suggested that epigenetic dysregulation in mitochondrial DNA (mtDNA) could contribute to the neurodegenerative process. We recently screened families with mutations in the major ALS causative genes, namely C9orf72, SOD1, FUS, and TARDBP, observing reduced methylation levels of the mtDNA regulatory region (D-loop) only in peripheral lymphocytes of SOD1 carriers. However, until now no studies investigated the potential role of mtDNA methylation impairment in the sporadic form of ALS, which accounts for the majority of disease cases. The aim of the current study was to investigate the D-loop methylation levels and the mtDNA copy number in sporadic ALS patients and compare them to those observed in healthy controls and in familial ALS patients. Pyrosequencing analysis of D-loop methylation levels and quantitative analysis of mtDNA copy number were performed in peripheral white blood cells from 36 sporadic ALS patients, 51 age- and sex-matched controls, and 27 familial ALS patients with germinal mutations in SOD1 or C9orf72 that represent the major familial ALS forms.ResultsIn the total sample, D-loop methylation levels were significantly lower in ALS patients compared to controls, and a significant inverse correlation between D-loop methylation levels and the mtDNA copy number was observed. Stratification of ALS patients into different subtypes revealed that both SOD1-mutant and sporadic ALS patients showed lower D-loop methylation levels compared to controls, while C9orf72-ALS patients showed similar D-loop methylation levels than controls. In healthy controls, but not in ALS patients, D-loop methylation levels decreased with increasing age at sampling and were higher in males compared to females.ConclusionsPresent data reveal altered D-loop methylation levels in sporadic ALS and confirm previous evidence of an inverse correlation between D-loop methylation levels and the mtDNA copy number, as well as differences among the major familial ALS subtypes. Overall, present results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and could represent compensatory mechanisms to counteract mitochondrial impairment in sporadic and SOD1-related ALS forms.

Dataset Information

Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis.

Publications

Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis.

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