title: 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.
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Shin
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Celine
authors.initials: C
authors.lastname: Bourdon
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Manon
authors.initials: M
authors.lastname: Bernard
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Canada, Department of Molecular Genetics.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wilson
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Reischl
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruggeri
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Sylvane
authors.initials: S
authors.lastname: Desrivieres
authors.affiliation: Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Leemans
authors.affiliation: Department of Epidemiology, Biostatistics and Occupational Health.
authors.forename: Michal
authors.initials: M
authors.lastname: Abrahamowicz
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Leonard
authors.affiliation: Department of Psychology, Université du Québec à Chicoutimi, Chicoutimi, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Richer
authors.affiliation: Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Canada, ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Chicoutimi, Canada.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bouchard
authors.affiliation: ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Chicoutimi, Canada, Department of Medicine, Université de Montréal, Montréal, Canada and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.affiliation: Rotman Research Institute, University of Toronto, Toronto, Canada, Child Mind Institute, New York, NY, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Paus
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Canada, Department of Physiology, Department of Nutritional Sciences, zdenka.pausova@sickkids.ca.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pausova
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002896:Chromosomes, Human, Pair 6; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D040641:Quantitative Trait Loci