Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, China

Author Of 1 Presentation

Genetics and Epigenetics Poster Presentation

P0526 - Methylome and transcriptome analysis implicates NBPF locus in PPMS etiopathology (ID 880)

Abstract

Background

Multiple Sclerosis is characterized by autoimmune destruction of myelin and neurons in the CNS leading to a variety of neurological symptoms. Primary progressive multiple sclerosis (PPMS) is characterized by accumulation of clinical disability from the onset, without relapses or remissions. The mechanisms underpinning MS progression are still largely unknown and specific clinical translations are lacking.

Objectives

To identify DNA methylation and gene expression changes that associate with progressive MS states using genetic, epigenetic and network analysis approaches.

Methods

Our methylome analysis in blood showed a striking increase in methylation at the NBPF locus specifically in PPMS (n=279, p=5x10-6), which was validated in independent samples. We then discovered that genetic variants determine methylation levels at this locus (p-val. range 10-21-10-13) and that the strongest variant potentially associates with the risk of developing PPMS (nPPMS=482, ncontrols=11718, p<0.03, OR=1.2). The same variant associated with reduced expression of FMO5, PRKAB2 and CHD1L in blood (n=156, p-val. range 10-7-10-2).

Results

Notably, a large body of evidence strongly implicate the identified locus in nervous processes involved in brain size and neuropsychiatric disorders. Thus, we hypothesize that it harbors the gene(s) that predispose for progressive disability in PPMS. To functionally confirm the identified differentially methylated region (DMR) can potentially regulate gene expression in a DNA methylation-dependent manner, we have used an in-vitro epigenetic reporter system and our data showed that the DMR region has properties of a gene-regulatory region. Moreover, we investigated the putative relevance of the genes included in the NBPF locus in PPMS brain pathology by constructing an unbiased correlation network analysis using RNA-sequencing data from brain tissue samples of MS patients (nPPMS=5 and nSPMS=7) and controls (n=10). Strikingly, identified gene modules were found centered on genes from the NBPF locus in PPMS. Indeed, exploration of the biggest module, revealed CHD1L as a major central node within this network. Gene ontology analysis of each module underscored implication in nervous processes. Thus, this unbiased in-silico approach further supports the potential implication of genes of NBPF locus in nervous processes in PPMS patients.

Conclusions

Our DNA methylation studies along with the unbiased network analysis approach using the transcriptome data independently suggest that the locus on chromosome 1 predisposes for PPMS.

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