Researchers Probe Genomes of Twins with Multiple Sclerosis for Nature vs. Nurture Clues

In a new study, researchers scoured the genomes of several identical twin pairs, in which one twin had developed multiple sclerosis (MS) while the other did not.  The researchers were searching for any genetic differences that could explain the twins’ different fates.

The study touches on the influence of nature vs. nurture in MS, which occurs when the body’s immune system inappropriately attacks the brain and spinal cord.  It has long been known that identical twins often have different outcomes when it comes to MS, a phenomenon called discordance.  This has been interpreted to mean that environmental factors must play a strong role in the disease.

However, as genetic technology has advanced, researchers have found that there are sometimes subtle genetic differences between identical, or monozygotic, twins.  (Monozygotic twins are derived from the fertilization of a single egg in their mother’s womb.)

The authors of the new study wondered if those differences might explain the discordance of MS in some monozygotic twins, but they were unable to find a genetic explanation.  The study was funded in part by the National Institutes of Health, and was published in Nature*.

“To date, this represents the most thorough genomic analysis of twins with an autoimmune disease.  The findings are intriguing not only for MS but for all studies that rely on twins to probe the roles of nature and nurture in complex diseases,” said Ursula Utz, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

“The study demonstrates the extent to which we might expect differences in the genomes of monozygotic twins,” said lead author Sergio Baranzini, Ph.D., an associate professor of neurology at the University of California San Francisco (UCSF).  The evident lack of differences should not be over-interpreted, Dr. Baranzini said.  Limitations of current technology may have caused the team to miss important genetic differences between twins.

Typical symptoms of MS include weakness, loss of vision and numbness or tingling sensations.  About 1 in 1000 Americans has the disorder.  Having a non-identical twin or other sibling with MS increases the risk to about 1 in 20, and having an identical twin increases the risk to about 1 in 4.  Those odds suggest a strong genetic component, but leave room for environmental risk factors, too.

One prominent theory is that a viral infection might trigger the immune reactions that underlie MS.  Each person’s unique genetic make-up would also influence these immune reactions and whether they lead to the disease.  While no viral trigger for MS has been confirmed, several genetic risk factors have been identified.

In the new study, Dr. Baranzini and his colleagues probed for differences in the genomes of three pairs of identical twins discordant for MS, using DNA from the twins’ T cells.  These are the cells responsible for launching the immune attack in MS.

The twin pairs in the study were 56, 39, and 19 years old when the study began in 2008.  The age of disease onset for the affected twins was 30, 38, and 13, respectively.  The unaffected twins showed no signs of the disease on MRI scans, and they have remained disease-free.  Prior research has found that when both twins in an identical pair develop MS, they usually have about the same age of onset.

The researchers started by checking the twins for known genetic risk factors for MS.  In one pair of twins, the researchers also scanned more than 99 percent of the genome, looking for new DNA variations that might be connected to MS.  In all three pairs, they scanned for small, known sites of variation called SNPs and for small DNA insertions, deletions or repeated sequences.  They looked for differences in gene expression, meaning whether a gene is turned on and how much it is turned on. They also looked for differences in epigenetics, or chemical modifications that can affect gene expression.  Finally, they looked for signs that viral genes had inserted into the affected twins’ DNA.

Between affected and unaffected twins, there were no reproducible differences in SNPs, other DNA changes, or gene expression levels.  Nor did affected twins have distinct signs of viral infection.  There were some differences in CpG methylation – a chemical tag at certain sites in DNA – between affected and unaffected twins, but none of those differences were observed in more than one twin pair.

The researchers noticed surprising differences between twins, but no correlation to MS, in a trait called allelic imbalance.  Most of our genes exist in two copies, or alleles.  Allelic imbalance describes a common situation where one copy of a gene is expressed at higher levels than the other copy.

“We found many instances where an allelic imbalance was larger in one twin than in the other, or where the imbalance was flipped between the two alleles,” said Dr. Baranzini.  Those differences were unexpected and are likely to be of interest in future studies of twins, whether the focus is on MS or other diseases, he said.

Dr. Baranzini is hopeful that one day, it will be possible to answer whether genetic differences contribute to different MS susceptibilities in identical twins.  He and his colleagues are planning to conduct deeper genome scans of more twins discordant for MS.

Other key members of the research team were Jorge Oksenberg, Ph.D., a professor of neurology at UCSF; Stephen Hauser, M.D., chair of neurology at UCSF; Gary Schroth, Ph.D., a senior director at Illumina, Inc. and Stephen Kingsmore, M.B., Ch.B., B.A.O., a physician-scientist and president of the non-profit National Center for Genome Resources in Santa Fe, N. M.

In addition to NINDS, the study received funding from NIH’s National Center for Research Resources (NCRR), the National MS Society, Small Ventures USA, Inc., the A.J. Brass Foundation, and the Nancy Davis Foundation.

– By Daniel Stimson, Ph.D.

*Baranzini SE et al.  “Genome, Epigenome and RNA Sequences of Monozygotic Twins Discordant for Multiple Sclerosis.”  Nature, April 29, 2010.