Ever since multiple sclerosis was first described in 1868, the cause of this persistent but unpredictable disease has been unclear. MS is partly heritable, but it seems also to require environmental triggers that spur the body to attack the insulation of its own nerve cells. Scientists have speculated that the genetic component of the disease might involve dozens of different genetic variations, all contributing a small amount of risk. So far, it has been difficult to verify such low-lying culprits.

A large-scale genomic study, published in the August 30 edition of The New England Journal of Medicine, has uncovered new genetic variations associated with the disease. The study—the most comprehensive analysis of the genetic basis of MS to date—was led by a consortium of investigators at several universities and medical centers, including HMS, the Broad Institute, and Brigham and Women’s Hospital. Although the genes account for just a small amount of individual risk, they point to molecular pathways that may underlie the disease and be potential treatment targets.

Confirming the Immune Connection

The only genetic link for MS that had been verified using traditional techniques is in the region encoding human leukocyte antigens (HLAs), a large cluster of genes that are responsible for preventing the body’s T cells from attacking its own tissues. One particular HLA haplotype has been linked to a higher risk of disease, but it does not occur in every case and does not necessarily cause MS. This analysis confirmed that HLA is the dominant genetic link, but went further to find other variants in genetic regions that are more common in people with MS.

The researchers gathered 931 trios of DNA samples from MS patients and their parents. They analyzed single nucleotide polymorphisms (SNPs), small differences in DNA sequence that represent the most common genetic variations among individuals, and looked for variations that were more commonly inherited by people with MS than by those without the disease. To double-check the findings, they performed a second analysis of other sets of families, individual cases of MS, and a control group. In the end, all the samples were combined for a final analysis of more than 12,000 subjects. David Hafler, a lead author of the paper and the Jack, Sadie and David Breakstone professor of neurology at HMS and Brigham and Women’s Hospital, said the replication was critical. “The majority of variants that looked significant in the first analysis disappeared,” he said.

The two regions that remained after the final analysis contain genes involved in the immune system, which lends another piece of evidence to the widely accepted hypothesis that MS is an autoimmune disease. One of the regions contains a gene that encodes the interleukin-2 (IL-2) receptor, which has also been linked to two other autoimmune diseases: type 1 diabetes and Graves disease. Hafler said that researchers have increasingly found commonalities between autoimmune diseases that affect different tissues in the body, including type 1 diabetes and rheumatoid arthritis. “This study will likely spur further research into the connection between these seemingly separate conditions,” he said.

Another region harbors a gene for the IL-7 receptor, which helps control the activity of regulatory T cells. The same variant was also linked to MS in two papers appearing simultaneously in Nature Genetics. One paper pooled data from many different studies to identify candidate genes, a technique the authors call “genetic convergence.” Jonathan Haines of Vanderbilt University, a co-author of the NEJM paper and senior author of the Nature Genetics paper, said that three independent studies arriving at the same pathway is exciting and adds weight to the importance of IL-7. “We got it in an unbiased way and a very biased way and we came up with the same thing,” he said. The variant seems to alter the ratio of membrane-bound and soluble forms of the receptor. Haines said that the findings will spur further research into the role this pathway plays in disease.

Tracing the Disease Network

The NEJM paper comes during a wave of genome-association studies attempting to uncover the genetic basis of complex diseases like diabetes, schizophrenia, and Parkinson’s disease. Unlike disorders caused by a mutation in a single gene, these seem to arise from a combination of inherited factors, behavior, and the environment, and scientists believe that a host of genetic variations may contribute to a person’s susceptibility. Because of this, the findings are more useful for pointing the way to the underlying cause of the disease than for determining an individual’s susceptibility.

In an accompanying editorial, Leena Peltonen of the University of Helsinki notes that it is “disappointing” that the two alleles found explain just 0.2 percent of the variance in risk of MS; and because they are very common, they cannot be considered major risk factors. Stephen Hauser, a paper co-author at the University of California, San Francisco, said that there are “other areas of interest, but we have not yet achieved statistical proof that they’re involved in the disease.” Part of the problem is amassing large enough datasets to detect subtle variations, a particularly difficult task for diseases as relatively rare as MS. The study was made possible by a large-scale collaboration among groups that had not worked together in the past, some of which had been collecting samples for decades. The consortium is planning to dig deeper with further studies that collect larger numbers of samples and scan more regions of the genome.

“People have been looking for genes involved in MS for 30 years,” Hafler said, “Why weren’t they found? The answer is, you couldn’t do it without the sequence of the human genome.” He compares the process to looking for stars during the day—the signals were too faint to be detected without the power of the genome sequence and subsequent haplotype map. Collecting larger numbers of samples will be the equivalent of seeing the stars with a telescope rather than the naked eye. “We’ve begun to find genes,” he said, “but there will be many more.”