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Large Multiple Sclerosis GWAS Points to Cell-Mediated Immunity Genes

By Andrea Anderson

NEW YORK (GenomeWeb News) – A large genome-wide association study published in Nature online today is implicating immune-related genes in multiple sclerosis risk.

Members of the International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium 2 teamed up to study samples from tens of thousands of individuals of European ancestry with or without MS from 15 countries. The GWAS confirmed almost two-dozen past genetic associations and pointed to 29 risk loci not found before.

Many of the variants fell in genes or pathways with ties to other autoimmune conditions, including Crohn's disease and type 1 diabetes. In particular, the GWAS implicated variants affecting genes in pathways contributing to the lymphocyte function, especially T-helper immune cell differentiation.

"What was very striking about our findings is that there's a massive over-representation, within the associated loci, of immune-related genes," co-corresponding author Peter Donnelly, director of the Wellcome Trust Centre for Human Genetics and WTCCC chair, told GenomeWeb Daily News.

"To us, that points pretty strongly to immune dysregulation as being a key part of the story for multiple sclerosis," he added.

As such, Donnelly noted, the new study is providing genetic clues about MS both by increasing the number of known loci outside the human leukocyte antigen region, which is known to be involved in MS genetics, and by clarifying the picture of genetic risk within the HLA. Previous studies have shown that genetic variation within HLA genes in the major histocompatibility complex (MHC), in particular HLA-DRB1, contributes to inherited MS risk.

"It's been known for a long time that there's a substantial genetic risk for multiple sclerosis in the MHC or the HLA," Donnelly said, "although there's been quite a lot of controversy and lack of clarity about exactly how that worked."

Likewise, the influence of genetic variants outside of the MHC region were not well understood, he and his co-authors noted, though more than 20 loci of small effect have been found through smaller GWAS efforts in the past.

Moreover, Donnelly said, there has been some debate over whether inflammation and immunological processes might cause damage to the myelin sheath surrounding the nerves in individuals with the disease or whether immune responses occur as a consequence of MS-related neurodegeneration.

To address such questions, the researchers decided to do a large GWAS involving 9,772 individuals of European descent with MS who were recruited in 15 countries by 23 research teams participating in the International Multiple Sclerosis Genetics Consortium. The 17,376 unaffected control samples, also from individuals with European ancestry, came from the WTCCC2 control set. Study participants were genotyped using the Illumina Human 660-Quad and Illumina 1.2 M platforms.

Because the study participants came from many countries, the researchers tested a few different approaches for addressing population structure and geographic variation patterns that might otherwise confound their results.

"The study was a bit unusual in terms of GWAS in having, as part of the primary study, cases from many populations, all broadly northern European," Donnelly explained, noting that it was not possible to assemble controls from the same populations for all of the MS cases studied. The team had varying success with the methods tested, he said, but ultimately found that an improved version of a linear mixed model was the most useful for their analyses.

Using data at more than 465,000 SNPs per sample, the researchers found 102 SNPs with potential MS associations outside of the MHC region. Most of these were also over-represented in a validation group comprised of another 4,218 cases compared to 7,296 more controls.

The GWAS data not only verified associations for 23 of the 26 loci implicated in previous studies, but also turned up 29 new loci with significant MS associations. Five other loci also appeared to correspond with disease risk, but were not statistically significant. Together, the variants identified so far explain an estimated 20 percent of genetic risk for MS.

In general, the findings support a role for immune function in MS, they reported, with roughly one-third of the MS-linked loci corresponding to regions of the genome that have also been implicated in other autoimmune diseases.

Genes involved in lymphocyte cell function and in the activation, proliferation, and differentiation of one type of lymphocyte in particular, T-helper cells, were especially common.

"Immunologically relevant genes are significantly over-represented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis," the study authors noted.

The researchers also found several SNPs in and around genes involved in cytokine and signal transduction pathways, genes involved in the metabolism of vitamin D, a proposed environmental factor in the disease, and genes involved in response to some MS treatments.

On the other hand, the team did not detect loci linked to birth month or gender. Nor did they find any variants corresponding to disease severity.

Within the MHC, the team used SNP data to impute information on the classical HLA alleles that are involved in MS — work that Donnelly said is helping to clarify researchers' understanding of how variation within HLA influences MS risk.

While they noted that more research is needed to better understand the interplay between genetic and environmental risk factors for MS and other conditions, those involved in the GWAS say the data to date are consistent with an important autoimmune role in the disease.

"Although our data do not address the issue of which components within the nervous system are initially damaged by the inflammatory response," the researchers wrote, "the over-representation of genes that influence T-cell maturation provides independent and compelling evidence that the critical disease mechanisms primarily involve immune dysregulation."

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