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Landmark Analysis Probes Nature vs. Nurture in Multiple Sclerosis

After an extensive genetic analysis, researchers were still unable to account for why, in 3 pairs of identical twins, one twin in each developed multiple sclerosis (MS) while the other didn't. The study represents the first female, twin and autoimmune disease genome sequences ever reported. The study doesn't question whether genes contribute to MS, but it strengthens the idea that environmental factors play an important role.

MS is an autoimmune disease in which the body’s own immune system inappropriately attacks the brain and spinal cord. Symptoms include muscle weakness, loss of vision, numbness or tingling, and difficulty with coordination and balance. In the worst cases, MS can produce partial or complete paralysis.

About 1 in 1,000 Americans has MS. Having a sibling with MS raises the risk to about 1 in 20; having an identical twin raises the risk to about 1 in 4. That suggests a strong genetic component to MS while leaving room for environmental risk factors, too.

A team lead by Dr. Sergio Baranzini at the University of California, San Francisco, set out to look for differences in the genomes of 3 pairs of identical twins in which one twin has MS and one doesn’t. The researchers used DNA from the twins’ T cells, which are responsible for launching the immune attack in MS.

In one pair of twins, the researchers scanned more than 99% of the genome, looking for new DNA variations that might be connected to MS. In all 3 pairs, they checked for genetic factors previously tied to MS. They scoured the genomes for tiny variations called single nucleotide polymorphisms (SNPs) and for small DNA insertions, deletions or repeated sequences that might be tied to MS. They also looked for differences in CpG methylation—a chemical modification to DNA that can affect gene expression. The work was funded in part by NIH’s ×îÐÂÂ鶹ÊÓƵ Institute of Neurological Disorders and Stroke (NINDS) and ×îÐÂÂ鶹ÊÓƵ Center for Research Resources (NCRR).

In the April 29, 2010, issue of Nature, the team reported finding no reproducible differences between affected and unaffected twins.

Viral infection has been proposed to contribute to MS, so the scientists looked for signs of viral genes inserted in the affected twins' DNA. They found no reproducible differences in viral DNA between the affected and unaffected twins, either.

The researchers did notice surprising differences between twins, albeit with no correlation to MS, in a trait called allelic imbalance. Most of our genes exist in 2 copies, or alleles. Allelic imbalance occurs when one copy of a gene is expressed at a higher level than the other. Allelic imbalances are likely to be of interest in future studies of twins, whether the focus is on MS or other diseases.

"To date, this represents the most thorough genomic analysis of twins with an autoimmune disease," says Dr. Ursula Utz, a program director at NINDS.

Baranzini says that even though they didn’t find genetic evidence for why one sibling would develop the disease while the other didn't, that doesn't necessarily mean there aren’t genetic differences between them. Current technology may not yet be able to detect them. The researchers are now planning even more detailed studies.