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Layered genetic control of DNA methylation and gene expression: A locus of multiple sclerosis in healthy individuals.
Hum. Mol. Genet. 24, 5733-5745 (2015)
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
ISSN (print) / ISBN
0964-6906
e-ISSN
1460-2083
Zeitschrift
Human Molecular Genetics
Quellenangaben
Band: 24,
Heft: 20,
Seiten: 5733-5745
Verlag
Oxford University Press
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Epidemiology II (EPI2)