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Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals.

ABSTRACT: DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300 kb region. The meQTL was identified in four samples (P = 2.8 × 10(-17), 3.1 × 10(-31), 4.0 × 10(-71) and 5.2 × 10(-199)), comprising a total of 2796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300 kb region (P = 7.1 × 10(-18)-1.0 × 10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: P = 2.4 × 10(-13)-7.1 × 10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis.

SUBMITTER: Shin J

PROVIDER: S-EPMC4581603 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals.

Shin Jean J Bourdon Celine C Bernard Manon M Wilson Michael D MD Reischl Eva E Waldenberger Melanie M Ruggeri Barbara B Schumann Gunter G Desrivieres Sylvane S Leemans Alexander A Abrahamowicz Michal M Leonard Gabriel G Richer Louis L Bouchard Luigi L Gaudet Daniel D Paus Tomas T Pausova Zdenka Z

Human molecular genetics 20150728 20

DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and ...[more]

PMID: 26220975

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Project description:BACKGROUND: Although there is substantial anecdotal evidence that clutter is common among people with multiple sclerosis (MS), the literature contains no reports of studies on the actual prevalence of the problem or its impact on functional performance in this population. Clutter promotes confusion and places individuals in potentially dangerous situations by increasing their risks of falling, losing medications, and misplacing important documents. In addition, it may negatively affect activities of daily living (ADLs). Many common MS symptoms such as decreased mobility, visual or cognitive changes, fatigue, and depression can exacerbate clutter accumulation, which in turn can have detrimental effects on physical, financial, emotional, cognitive, and social functioning. It is critical for MS clinicians to address clutter management in order to improve patients' overall functional independence and participation. METHODS: A clutter reduction protocol was developed and implemented at our institution for individuals with MS. Our group program addresses psychosocial issues preventing organization and offers practical strategies for clutter removal and management to improve performance in ADLs. A clutter questionnaire is administered to individuals before and after their participation in the group program. RESULTS: Anecdotal reports indicate that the intervention helped to reduce clutter, promote a more realistic attitude toward "possessions," and establish a sense of accomplishment in controlling one's environment. Participants also reported fewer falls, feeling less isolated, increased ease in finding their medications, and a general sense of cognitive clarity in accomplishing ADLs. Outcome assessments are now being developed to objectively measure these effects as well as the prevalence of clutter within the MS population. CONCLUSIONS: Clutter management is an important area for MS clinicians to address because it can significantly affect patients' functioning, safety, performance of ADLs, and quality of life.

Dataset Information

Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals.

Publications

Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals.

Similar Datasets

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