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

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.