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Shin, J.T.* ; Bourdon, C.* ; Bernard, M.* ; Wilson, M.* ; Reischl, E. ; Waldenberger, M. ; Ruggeri, B.* ; Schumann, G.* ; Desrivières, S.* ; Leemans, A.* ; Abrahamowicz, M.* ; Leonard, G.T.* ; Richer, L.* ; Bouchard, L.* ; Gaudet, D.* ; Paus, T.* ; Pausova, Z.*

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

Hum. Mol. Genet. 24, 5733-5745 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 (<3kb). 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=2.8x10(-17), p=3.1x10(-31), 4.0x10(-71), 5.2x10(-199)), comprising a total of 2,796 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=7.1x10(-18)-1.0x10(-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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 24, Issue: 20, Pages: 5733-5745 Article Number: , Supplement: ,
Publisher Oxford University Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)