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Novel Multiple Sclerosis Susceptibility Loci Have Epigenetic Regulation Links

NEW YORK (GenomeWeb) – Through a genome-wide association study, a German-led team of researchers has uncovered novel multiple sclerosis susceptibility loci that are also linked to epigenetic regulation.

The Max Planck Institute of Psychiatry's Bertram Müller-Mysok and his colleagues conducted a GWAS of nearly 5,000 people with multiple sclerosis and more than 10,000 controls. As the researchers reported in Science Advances today, they linked 15 loci outside of the major histocompatibility complex to MS susceptibility, including four loci that hadn't before been associated with the disease. Recent studies have further suggested that these loci have roles in epigenetic regulation.

"As epigenetic mechanisms constitute a major route for environmental risk factors to influence expression of disease-associated genes, regulation of DNA and protein methylation is an interface where genetic and environmental risk factors for MS might intersect," Müller-Mysok and his colleagues wrote in their paper.

The team recruited two cohorts, one with 3,934 patients and 8,455 controls and the other with 954 cases and 1,940 controls. Both cohorts were imputed to the 1,000 Genomes Phase I data to yield more than 8 million variants. The researchers conducted a separate GWAS on each cohort.

In a pooled analysis, the researchers uncovered associations both within and outside the MHC region. Outside the MHC, 15 loci exhibited genome-wide significance, 10 of which had previously linked to MS in a different GWAS study, and one of which — DLEU1 — had been linked to MS through a candidate gene study. The remaining four were novel MS susceptibility loci, according to the team.

To validate these variants, the researchers then compared their findings to those from another, larger MS study. Some 104 variants were analyzed in both studies, and they all exhibited the same direction of effect. In addition, they examined the lead variants at these four novel MS susceptibility loci and DLEU1 in an independent cohort of 2,903 cases and 3,323 controls from Sardinia. Two variants, rs2812197 and rs4925166, could be replicated, while the other two exhibited the same direction of effect, but didn't reach significance.

The association at rs4925166 was the strongest of the novel loci, Müller-Mysok and his colleagues said, noting that it exhibited an odds ratio of 0.85 in the pooled German cohort. They traced this SNP to chromosome 17 and an intron of the TOP3A gene, which encodes the DNA topoisomerase IIIα.

But as there were other strongly associated SNPs in this region, the researchers conducted an eQTL analysis and found that the variant at rs4925166 and the proxy SNPs were part of a strong eQTL with the SHMT1 gene. This eQTL was replicated in two independent datasets and in an eQTL database.

They further found eight methylation QTLs between rs4925166 and CpGs in SHMT1 in a dataset from the Max Planck Institute of Psychiatry, and three of these MQTLs could be replicated in the Grady Trauma Project dataset. Through this and further analyses, the researchers concluded that rs4925166 affects SHMT1 gene expression in a complex manner.

Müller-Mysok and his colleagues traced the three other novel loci to an intron of L3MBTL3, an intron in ERG, and to an intron in the gene MAZ, respectively.

While each of the genes associated with the four novel multiple sclerosis susceptibility loci and DLEU1 have known roles in regulatory processes of the immune system, the researchers noted that there's been both direct and indirect evidence also linking them to epigenetic regulatory mechanisms.

For instance, L3MBTL3 recognizes epigenetic histone lysine methylation and ERG interacts with the histone H3–specific methyltransferase ESET. Meanwhile, SHMT1 helps to maintain methylation homeostasis in the cell as it catalyzes a key reaction in the creation of the methyl donor substrate SAM.

"By finding novel risk genes with potential roles in epigenetic regulation, our study adds further indication that epigenetic mechanisms might be important for MS susceptibility," Müller-Mysok and his colleagues wrote. "A disturbed homeostasis of methyl donors, caused by an altered expression of SHMT1, is likely to have an impact on the disease."