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Hum Mol Genet. 2015 Oct 15;24(20):5733-45. doi: 10.1093/hmg/ddv294. Epub 2015 Jul 28.

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

Author information

1
The Hospital for Sick Children, University of Toronto, Toronto, Canada.
2
The Hospital for Sick Children, University of Toronto, Toronto, Canada, Department of Molecular Genetics.
3
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany.
4
MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
5
Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
6
Department of Epidemiology, Biostatistics and Occupational Health.
7
Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
8
Department of Psychology, Université du Québec à Chicoutimi, Chicoutimi, Canada.
9
Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Canada, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Chicoutimi, Canada.
10
ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Chicoutimi, Canada, Department of Medicine, Université de Montréal, Montréal, Canada and.
11
Rotman Research Institute, University of Toronto, Toronto, Canada, Child Mind Institute, New York, NY, USA.
12
The Hospital for Sick Children, University of Toronto, Toronto, Canada, Department of Physiology, Department of Nutritional Sciences, zdenka.pausova@sickkids.ca.

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.

PMID:
26220975
PMCID:
PMC4581603
DOI:
10.1093/hmg/ddv294
[Indexed for MEDLINE]
Free PMC Article

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