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

Shin, Jean, Bourdon, Celine, Bernard, Manon, Wilson, Michael D., Reischl, Eva, Waldenberger, Melanie, Ruggeri, Barbara, Schumann, Gunter, Desrivieres, Sylvane, Leemans, Alexander, Abrahamowicz, Michal, Leonard, Gabriel, Richer, Louis, Bouchard, Luigi, Gaudet, Daniel, Paus, Tomas, Pausova, Zdenka


Human Molecular Genetics 24 (20), p. 5733-5745


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 allelewas associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a longrange meQTL that controls methylation and expression of several genes andmay be involved in increasing brain vulnerability to multiple sclerosis.