Research teams uncover risk genes for Multiple Sclerosis

Two new large-scale genomic studies have honed in on the main genetic pathway associated with multiple sclerosis (MS), while also uncovering new genetic variations in the disease and suggesting a possible link between MS and other autoimmune diseases.

The first study, led by an international consortium of clinical scientists and genomics experts, incorporates the two largest collections of MS genetic information worldwide and is the first comprehensive study to investigate the overall genetic basis of MS. Its findings appear in the July 29, 2007 online edition of the “New England Journal of Medicine”.

Another study is being published simultaneously on the web site of “Nature Genetics,” and focuses on one variant in a gene called interleukin-7 receptor (IL-7R), which researchers had thought was connected to the disease and now know increases the risk of MS.

“Scientists have known for 30 years that genetics play a critical role in MS, but the disease is influenced by so many different factors that it has consistently eluded us,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco and an author on both papers. “It wasn’t until we could map genomes and then combine the efforts of dozens of researchers, that we could put all the pieces together.”

Together, he said, these two papers illustrate how scientific collaboration and the recent breakthroughs in genomic technology, which make it possible to both screen an individual’s genetic architecture and understand the differences, can open up an age-old disease such as multiple sclerosis.

It is significant that the two studies used very different approaches, but both highlighted the role of IL-7R, he said.

“Together, these place the IL-7R pathway at the center of understanding MS pathogenesis,” Hauser said. “I believe that this receptor and its interaction with regulatory T cells will now become a major focus of research on MS.”

The NEJM paper involved a hypothesis-neutral approach, in which the research teams scanned the entire genome of MS patients, their families and a control group for similarities and differences. By contrast, the “Nature Genetics” paper hypothesized that IL-7R was significant and focused on that portion of the genome to assess whether it was, in fact, a key factor in the MS patients.

MS is a disease of the central nervous system whose symptoms range from mild muscle weakness to partial or complete paralysis. It is widely considered an autoimmune disease that arises from a combination of genetic and environmental factors. This collusion of events leads the body to attack and destroy the insulation along nerve fibers.

The consortium study, reported in NEJM, was co-led by researchers at UCSF and five other universities and medical centers in the United States and England. The team analyzed genomic information from 12,360 people and confirmed that immune system genes are altered in people diagnosed with MS. It also pointed to potential mechanisms of the disease.

This study analyzed single nucleotide polymorphisms (SNPs), which are small differences in the DNA sequence that represent the most common genetic variations between individuals. The team looked for variations that were more commonly inherited by people with MS compared to samples from people without the disease.

Until now, the only genetic link identified with MS was in the major histocompatibility complex (MHC), a large cluster of genes responsible for many immune functions, including preventing the body’s immune cells from attacking its own tissues. This analysis confirmed that link while also finding other variants in genetic regions that are more common in people with MS.

“Scientists are increasingly finding genetic links between autoimmune diseases that affect different tissues in the body, including type 1 diabetes and rheumatoid arthritis,” said David Hafler, MD, the Jack, Sadie and David Breakstone professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, another of the consortium study authors. “This study will likely spur further research into the connection between these seemingly separate conditions.” 

These advances are an outgrowth of a 15-year effort at UCSF to create a national repository of more than 10,000 samples of DNA from people with MS and their families, the largest such collection nationwide. A similar database, in both quantity and quality, had been developed at the University of Cambridge, in England. Both collections were used for both of these studies.

But the real breakthroughs came through collaboration. Hauser said that individually, none of the six centers in the consortium could have completed a study of this scale and complexity, but by using a Collaborative Research Award from the National MS Society, they were able to form a truly effective international consortium that could deliver the most exhaustive search for MS risk factors ever published.

The consortium paper is among a series of recent whole-genome association studies that have begun to uncover the genetic basis of complex diseases like diabetes, schizophrenia, and coronary artery disease. Unlike diseases caused by a mutation in a single gene, these conditions seem to arise from a combination of genetic, behavioral and environmental factors.

Jorge Oksenberg, PhD, a UCSF neurology professor who has been involved in the development of the UCSF collection for more than a decade, said that it wasn’t until scientists were able to combine the potential of both repositories with the intellectual and financial resources of previously competing research teams that they were able to make the connections represented in these studies.

“For studying these complex genetic diseases, where we’re looking at many genes contributing and each one contributing just a little bit, we need a very large group of patients and controls,” said Oksenberg, who, along with Hauser, worked on both the consortium research and the study for the “Nature Genetics” paper. “We’re looking for genetic markers that we know are common in the population at large, but they’re somehow more common in the MS patients, and when combined, they make the patient more susceptible to getting MS.”

Genomic technologies have now made it possible to uncover these subtle genetic associations. The next step is to begin to collect larger numbers of samples and examine more DNA sequences, which will allow scientists to identify subtler variations that contribute to the disease.

“Despite all the hype and new technology, the genome is still mysterious to us,” Oksenberg said. “This has opened a new window into MS genetics. Now we need to understand what these chains are doing.”

The international collaboration is currently planning even larger and more detailed explorations of the genetic landscape of MS and is now committed to making the entire data set available to MS researchers worldwide.

This work was supported by grants from the National Multiple Sclerosis Society, National Institutes of Health, the Nancy Davis Center Without Walls, and the Penates Foundation.

The other lead investigators on the NEJM study are Alastair Compston, University of Cambridge School of Clinical Medicine, United Kingdom; Eric S. Lander, Broad Institute of Harvard University and Massachusetts Institute of Technology; Margaret A. Pericak-Vance, University of Miami School of Medicine; and Jonathan L. Haines, Vanderbilt University Medical Center.

Other investigators in the “Nature Genetics” study are Simon G. Gregory, Silke Schmidt, Puneet Seth, John Hart, Angela Prokop, and Mariano A. Garcia-Blanco, Duke University Medical Center; Stacy J. Caillier and Robin Lincoln, UCSF;  An Goris and Benedicte Dubois, Katholieke Universiteit Leuven, Belgium;  Lisa F. Barcellos, UC Berkeley; Jacob L. McCauley and Jonathan L. Haines, Vanderbilt University Medical Center; Stephen J. Sawcer, Maria Ban and Alastair S. Compston, University of Cambridge School of Clinical Medicine, UK; and Margaret A. Pericak-Vance, University of Miami School of Medicine.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.

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ADDITIONAL CONTACTS FOR NEJM PAPER:

Brigham and Women’s Hospital: Kevin Myron, [email protected], 617.534.1600

Broad Institute of Harvard and MIT: Nicole Davis, [email protected]

Harvard Medical School: David Cameron, [email protected], 617.432.0442

National Multiple Sclerosis Society: Arney Rosenblat, [email protected], 212.476.0436

University of Cambridge School of Clinical Medicine: Genevieve Maul, [email protected],
+44 (0) 1223 332300

University of Miami School of Medicine: Omar Montejo, [email protected], 305.243.5654

Vanderbilt University Medical Center: John Howser, [email protected], 615.322.4747

ADDITIONAL CONTACTS FOR NATURE GENETICS PAPER:

Vanderbilt University Medical Center: Jonathan Haines, [email protected] ,
615.343.5851