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Identification of differential DNA methylation associated with multiple sclerosis: a family-based study

ABSTRACT: Multiple Sclerosis (MS) is known to be caused by a genetic predisposition triggered by environmental factors. Despite the knowledge of genetic factors and environmental agents involved, it is largely unclear how they interact. Epigenetics, particularly DNA methylation, represents a model for environmental factors to influence the genome. In this paper, we studied 26 affected and 26 unaffected relatives from 8 MS multiplex families (≥ 3 affected relatives) as part of a multicentric Italian cohort study using Methylated DNA immunoprecipitation sequencing (MeDIP-Seq) run on an Illumina® HiSeq 2500 (2x100 bp). Technical validation in 6/8 of the original families and biological replication in 2 additional families (FDR < 0.1 and a concordant fold change, FC) were performed in suggestive differentially methylated regions (DMRs) between affected and unaffected relatives using SeqCap Epi Choice Enrichment (Roche®). Evidence of association from MeDIP-Seq across 8 families was combined with aggregation statistics, separately for hypo- and hyper-methylated regions with concordant FC in ≥ 6/8 families, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypomethylated regions, which point to NTM and BAI3 genes, and 2 hypermethylated regions in PIK3R1 and CAPN13 (mean size: 3.1 kb). Multiplex families represent a privileged setting for the study of regions of differential methylation as they reduce the impact of potential confounders like shared genetics and environmental factors. We identified 4 novel regions which contain genes of potential interest that need to be tested in larger cohorts of patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149562 | GEO | 2021/05/01

REPOSITORIES: GEO

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Project description:Previous studies examining the reproductive health of alligators in Florida lakes indicate that a variety of developmental and health impacts can be attributed to environmental quality and exposures to environmental contaminants. A number of these environmental contaminants have been shown to disrupt normal endocrine signaling. The potential that these environmental toxicants may influence epigenetic status and correlate to the health abnormalities was investigated in the current study. The red blood cell (RBC) (erythrocyte) in the alligator is nucleated so was used as an easily purified marker cell to investigate epigenetic programming. RBCs were collected from adult male alligators captured at three sites in Florida, each characterized by varying degrees of contamination. While Lake Woodruff (WO) has remained relatively pristine, Lake Apopka (AP) and Merritt Island (MI) convey exposures to different suites of contaminants. DNA was isolated and methylated DNA immunoprecipitation (MeDIP) was used to isolate methylated DNA that was then analyzed in a competitive hybridization using a genome-wide alligator tiling array for a MeDIP-Chip analysis. Pairwise comparisons of alligators from AP and MI to WO revealed alterations in the DNA methylome. The AP vs. WO comparison identified 85 differential DNA methylation regions (DMRs) with ≥3 adjacent oligonucleotide tiling array probes and 15,451 DMRs with a single oligo probe analysis. The MI vs. WO comparison identified 75 DMRs with the ≥3 oligo probe and 17,411 DMRs with the single oligo probe analysis. There was negligible overlap between the DMRs identified in AP vs. WO and MI vs. WO comparisons. In both comparisons DMRs were primarily associated with CpG deserts which are regions of low CpG density (1-2 CpG/100bp). Although the alligator genome is not fully annotated, gene associations were identified and correlated to major gene functional categories and pathways. Observations demonstrate that environmental quality is associated with epigenetic programming and status in the alligator. The epigenetic alterations may provide biomarkers to assess the environmental exposures and health impacts on these populations of alligators.

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Identification of differential DNA methylation associated with multiple sclerosis: a family-based study

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