Multiple Sclerosis: Is it in our genes?

Our understanding of the genetic basis of multiple sclerosis has taken off over the past few years. Admittedly, the first link between MS and our genes was made in the early 1970s when scientists identified a set of immune-related genes that they found to be associated with an increased risk of MS. However, it wasn’t until the last ten years that a combination of advances in genetic sequencing technology, the bringing together of large population datasets, and bolstered by insights from the genetic blueprint constructed by the Human Genome Project, really put MS genetics on the map. Today, researchers to date have discovered over 100 genetic variants that have been linked to an increased risk of MS, and the overwhelming majority of these variants contain instructions for making proteins that influence the immune system. Individually, these variants only influence risk by a very small degree, and researchers are continuing to piece together the ways in which these genes interact and how they’re influenced by the environment to build up to a tipping point for triggering MS.

At the same time that scientists have been searching for genetic risk factors for MS, another story has been gradually unfolding since the 1980s looking at how MS is inherited within families. A pioneer in this field is Dr. Dessa Sadovnick from the University of British Columbia, who’s devoted her career to answering the question of why and how MS appears to cluster among relatives in certain families. Her early studies gathered enough evidence to build a strong case for receiving a $2.2 million grant by the MS Society and its affiliated MS Scientific Research Foundation to fund The Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS). A crucial outcome of this project was the development of one of the largest and richest MS genetic databases in the world encompassing over 30,000 people with MS and their relatives from 15 MS Clinics across Canada.

Dr. Dessa Sadovnick

Dr. Dessa Sadovnick

Along with her collaborator Dr. George Ebers (then based at Western University), Dr. Sadovnick’s research gave us important insights into the risk of MS in first-, second- and third-degree relatives of people living with MS. Their research also involved observing married couples and adopted siblings (who have a comparatively lower risk of MS than blood relatives) in families with cases of MS; this led to compelling evidence that the risk of MS among relatives had a clear genetic component that was stronger than the influence of a shared environment. One question for which there was no satisfying answer asks how exactly is MS risk is passed on, since there was no evidence that MS is strictly hereditary – after all, while an identical twin of someone with MS (who carries identical genes) is much more likely to also have the disease (the odds are about 1 in 4), the chances aren’t 100% as we would expect. As the CCPGSMS carried on, Dr. Sadovnick and her team explored how a person’s genes and their environment interacted to modify their risk of developing MS.

These two parallel stories of MS genetic risk factors and familial inheritance converged in a new study published today in the journal Neuron by Dr. Sadovnick and her collaborators, including Dr. Carles Vilariño-Güell who spearheaded the genetic analysis used in the study. Using information that was scoured from the rich dataset captured by the CCPGSMS biobank, Drs. Vilariño-Güell, Sadovnick and their team were able to home in on a single genetic mutation that was strongly linked to a specific, aggressive form of progressive MS found in multiple relatives of two unrelated families. Details about the study, its findings and implications for people affected by MS are included in the latest MS Update.

The MS Society research team had the opportunity to ask Dr. Sadovnick a number of important questions about her study. In particular, Dr. Sadovnick answers important questions like “what happens if you inherit this specific genetic mutation?” and “what will be the impact of these findings for people affected by MS?”. Keep reading for an excerpt from our interview.

1. What is your study telling us in terms of genetic risk factors for MS? How did the technique used in the study demonstrate a genetic link?

Identifying a genetic link to MS has been ongoing for some time.  Once it was recognized that biological relatives had MS more often than the general population (data from adoptee, step-siblings, conjugal MS studies – much of data from Canadian Collaborative Project on Genetic Susceptibility to MS (“CCPGSMS”) funded by the MS Society of Canada and MS Scientific Research Foundation), it was important to identify if this increase was due to shared family environment or genetics.  Family studies clearly showed that the amount of DNA (genetic) sharing was critical to the risk for family members to develop MS (again many studies from the CCPGSMS including twins, half-siblings, aunts/uncles/nieces, nephews etc.).

 Once the importance of DNA sharing was recognized in familial risks to develop MS, the search began for genes that cause MS.  This was done by looking at large populations of persons with MS and family studies on affected and unaffected family members.  Over time, technology advanced (time, costs, and methods) from linkage studies to genome wide association studies (GWAS) to the current state-of-the-art exome sequencing.  It was through this advanced technique that we were able to identify the genetic mutations in two families.

2. Do these findings mean that if you inherit the specific genetic mutation you are likely to develop MS?

This finding means that if you have inherited the mutation you have a very high chance (60-70%) to develop the same type of MS (primary progressive) observed in these families at some point in your lifetime.

3. Do these findings mean MS is inherited?

As with other adult onset common complex disorders (e.g. Alzheimer disease, breast cancer, etc.), there are most likely some families, like the two described in this study, where MS is inherited and persons in these families with this genetic change have a very high risk for MS (about 60-70%). These families account for approximately 15% of all people living with MS. However, again similar to other adult onset common complex disease, the majority of MS will be the result of gene/environment interaction rather than a single genetic change.

4. How may these findings influence clinical practice (i.e. genetic screening, diagnostics, prevention strategies and/or targeted therapeutics)?

Again, it must be emphasized that to date these findings are in two large families with primary progressive MS.  Specific to these families, genetic screening/genetic diagnosis can be offered with the appropriate genetic counselling common to any single gene disorder where clinically unaffected individuals are identified.  Finding this genetic change in an unaffected family member allows for the screening of MS brain lesions using magnetic resonance imaging (MRI) indicating the development of MS before the onset of clinical symptoms.  Thus in these families, genetic testing may allow the earlier start of MS therapies. [However], unlike “risk” susceptibility genetic screening (such as that offered by [consumer genetic testing companies]), this appears to be a causal genetic change which is entirely different and when it can be offered in specific families, much counselling is required both pre- and post-testing – it is not a situation where you simply send off a blood sample.

For the MS population in general, understanding how this genetic change works can be critical in designing targeted therapies, specifically for primary progressive MS for which current disease modifying therapies are not available. Interestingly, novel therapeutics targeting this gene have been developed for the treatment of atherosclerosis, coronary heart disease, diabetes, and neurodegenerative diseases; and they may be repurposed for the treatment of patients with MS. We are in the process of obtaining an animal model with the genetic mutation identified in people living with MS. The study of this model will lead to a better understanding of the underlying processes responsible for the onset of MS and provide the tools to assess the effectiveness of novel therapeutics.

Questions or comments? Leave them below!

References

  1. Jersild C. et al. HL-A antigens and multiple sclerosis. Lancet. 1972;1(7762):1240-1.
  2. Dyment D.A. et al. Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Hum Mol Genet. 2005;14(14):2019–26.
  3. Sadovnick A.D. et al. Multiple sclerosis: updated risks for relatives. Am J Med Genet. 1988;29(3):533-41.
  4. Sadovnick A.D. et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol. 1993;33(3):281-5.
  5. Ebers G.C. et al. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature. 1995;14;377(6545):150-1.
  6. Wang Z. et al. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron. 2016;90:948–954.

6 thoughts on “Multiple Sclerosis: Is it in our genes?

  1. Diane

    I found your article interesting as my husband, my son and my daughter all have MS. I have been told in the past that the genetic component for inheriting MS was very small (1-2%) but given your studies it is much higher than that.
    thank you

    Reply
    1. drkarenlee Post author

      Hi Diane,

      An important thing to keep in mind is that MS is a complex disease that’s likely influenced by a combination of various genetic, biological and environmental factors. Based on this latest study, individuals that carry these gene mutation have a greatly elevated risk (up to 70%) of developing this specific form of progressive MS; however, this mutation is also very rare (about 1 in 1,000 in people living with MS carry it), and based on what we know so far, the contribution of other risk genes in most people is indeed relatively small. We’re hoping that as the sophistication of genetic sequencing technology goes up and costs go down, researchers will be able to uncover more insights into the genetic component of MS.

      Dr. K

      Reply
  2. F.E.

    I would be interested in hearing Dr. Sadovnick’s response to criticism alleging gross inadequacies in the data and evidence given in the study, in relation to the claim that is being made (i.e. that NR1H3 R415Q is a strong MS-risk genotype, indeed here Dr. Sadovnick is claiming a lifetime MS-risk of 60-70%, for developing MS).

    I am referring specifically to the criticism by Daniel MacArthur and Chris Cotsapas (see for example the Pubmed Commons discussion at http://www.ncbi.nlm.nih.gov/pubmed/27253448 or the rebuttal at http://biorxiv.org/content/early/2016/06/29/061366). To me, the counter-evidence of missing allele enrichment is highly persuasive. Certainly a lifetime MS-risk in heterozygotes of 60-70% is not reflected in Cotsapas analysis of the larger IMSGC collective.

    Reply

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