Researchers mine MS Scientific Research Foundation-funded biobank to discover a genetic mutation associated with an aggressive form of primary progressive MS

REVISION: June 3, 2016


The precise factors that cause multiple sclerosis continue to puzzle researchers today, although the prevailing view is that a combination of genetic, biological, and environmental factors interacts to trigger the emergence of the disease. Over the past three decades, researchers have closely observed trends in population patterns which, in combination with increasingly sophisticated genetic technology, have allowed them to probe the genetic basis of MS.

A series of seminal studies that began in the late 1980s, led by Dr. Dessa Sadovnick from The University of British Columbia (UBC) and Dr. George Ebers who at the time was based at Western University, built a strong case that genetic factors play an important role in the risk for MS. Their research showed that biological first degree relatives of someone living with MS had a significantly elevated risk of developing the disease compared to the general population. Moreover, a shared environment – such as common exposure to certain environmental factors in the same household – could not account for this family clustering of risk. These promising discoveries led to the launch of The Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS) in 1993. This large-scale, multi-site initiative funded by the MS Society and MS Scientific Research Foundation involved the collection of blood samples and clinical information from over 4,400 people with MS along with 8,600 blood relatives from across Canada, becoming one of the largest MS genetic biobanks in the world. With this information the researchers identified genes linked to MS risk, mapped out patterns of MS among family members, and determined how genetic risk factors are influenced by the environment.

In a study published this week in the journal Neuron, a research team that included Dr. Sadovnick as well as collaborators Drs. Carles Vilariño-Güell, Weihong Song and Anthony Traboulsee (UBC) used information mined from the CCPGSMS biobank to identify a single genetic mutation that was strongly associated with a specific form of severe, progressive MS. Using sophisticated genetic sequencing techniques, the team also determined the biological pathways that are controlled by the gene mutation, providing a window into the MS disease process in those individuals.

The Study and Results

The researchers started with a sample set of 2,053 people living with MS and 799 unrelated healthy controls (used for comparison), whose blood samples were available through the CCPGSMS biobank. Clinical records were evaluated to identify families with multiple cases of MS that had similar characteristics. The researchers narrowed down the list to a large family in which several relatives across multiple generations exhibited an aggressive form of either primary progressive MS or a secondary progressive form that rapidly followed a relapsing remitting course within three years of onset.

Using a sophisticated and powerful genetic sequencing technique, the researchers identified a mutation in a specific gene called NR1H3 in members of the family who were diagnosed with an unusual, aggressive form of progressive MS.

Once they had narrowed in on a specific genetic mutation, the researchers then expanded their analysis to look for the mutation among 2,053 people living with MS and 799 healthy controls. This allowed them to identify a second unrelated family with a carrier of the mutation who also experienced a similar course of aggressive, primary progressive MS. Since the family members carrying the mutation who were not diagnosed with MS were lost to follow up, the researchers could not rule out whether those individuals went on to develop MS later in life or if their diagnosis was missed according to the criteria at the time. Overall, the researchers found that across the two families, the risk of developing this form of MS for people carrying the mutation was between 60 – 70%.

The researchers examined the NR1H3 gene in more detail to determine its function in the body and uncover its potential role in MS. Their analysis revealed that NR1H3 contains the blueprints that tell the body to produce a protein called LXRA. This protein is thought to act as a switch for other genes involved in MS, such as those that control remyelination and inflammation.


Over the past decade or so, increasingly state-of-the-art genetic analysis technologies have allowed researchers to assemble a catalogue of over 100 genetic risk factors that are associated with the risk of developing MS. To date, these genes account for a small contribution to overall disease risk and only paint part of the picture in terms of the hereditary nature of MS. This new study by Dr. Sadovnick and her collaborators have uncovered an important missing piece to the puzzle, as these findings address important questions about how certain forms of MS are genetically passed on by parents to their offspring. An important note is that this specific NR1H3 mutation appears to be extremely rare, being present in only 0.1% of the MS population captured by the CCPGSMS biobank. According to the authors, in the overwhelming majority of people living with MS, their disease is most likely the result of an interaction between various genetic and environmental triggers rather than a single mutation.

The mechanism by which the NR1H3 mutation triggers and/or drives this form of progressive MS is the subject of ongoing study. Based on their observations, the researchers speculated that certain individuals carrying the mutation might experience a “one-two punch” in response to myelin damage in the form of both an intensified inflammatory response as well as impaired myelin repair. The combination of these factors would lead to a perfect storm in which nerve fibres lacking the protective myelin sheath would undergo neurodegeneration and rapidly progressing disease.

The results of this study may have important implications for future screening, diagnostics and prevention strategies. In their interpretation of the results, the researchers indicate that in people who don’t live with MS but have a strong family history of the disease, screening for the NR1H3 gene could help clinicians decide whether to perform diagnostic imaging to test for evidence of disease in the brain before the emergence of visible symptoms. The researchers note that another benefit of the study is that it could lead to a new genetic animal model for primary progressive MS that could allow researchers to better understand the underlying disease mechanisms and design drugs that target this gene with the aim of developing therapeutic approaches to progressive forms of MS.


Wang Z et al. (2016) Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron. 90:948–954