ACTRIMS 2022 | The genetic basis of multiple sclerosis severity
Adil Harroud, MD, University of California, San Francisco, San Francisco, CA, talks on an investigation into the contribution of genetics to disease severity in multiple sclerosis (MS). There is currently a wide breadth of knowledge covering genetic susceptibility of MS, however, little is known about the genetic contributions to disease progression. To address this, a study was conducted including 13,000 patients with MS, in which their genetic information was assessed in conjunction with clinical data. The study advanced the field of MS genetics, demonstrating for the first time that MS severity can be heritable, which was measured based on the age-related MS severity score to account for differences in age. Additionally, the genetic effects of MS susceptibility and severity were compared via genetic correlation across the entire genome. Genetic correlation was found to be low, concluding genetic influences of susceptibility and genetic influences of severity are not the same. This interview took place at the ACTRIMS Forum 2022 in West Palm Beach, Florida.
Transcript (edited for clarity)
We know that the key challenge in the field currently is understanding and treating progression in MS. We think that genetics can contribute to addressing these questions. Genetics have the unique ability to get to root causes. There are also multiple studies that have shown that drug targets that have supportive genetic evidence are twice as likely to reach regulatory approval and success in clinical trials than those that don’t have genetic support...
We know that the key challenge in the field currently is understanding and treating progression in MS. We think that genetics can contribute to addressing these questions. Genetics have the unique ability to get to root causes. There are also multiple studies that have shown that drug targets that have supportive genetic evidence are twice as likely to reach regulatory approval and success in clinical trials than those that don’t have genetic support.
So far, we know a lot about genetic susceptibility to MS, why people develop MS, but we know very little about what genetic contributions there are to the disease course and to how people fare once they have MS. We don’t even know if those genetic influences exist, so we thought it was really important to address this question, to study a large cohort of individuals with MS, and be able to assess their progression.
The study included about 13,000 people with MS for whom we had both clinical details, as well as whole genome genotyping, so we were able to assess their genetic information. This was collected through the international MS Genetics Consortium, which is a consortium that groups sites from across North America, Europe, Australia, and New Zealand. With the support of my supervisors, Sergio Baranzini and Stephan Sawcer, we looked at all of this clinical information in both a cross-sectional and longitudinal manner and analyzed their whole genome based on whole genome genotyping.
We were able to make a few key advances in the field of MS genetics. The first is that we were able to show, for the first time, that severity in MS is heritable, that there is a genetic contribution. We measured that to be about 13-14% of the variability in outcomes that we measure based on the age-related MS severity score to account for differences in age. We know that the true numbers likely higher, because we’re not able to account for very rare genetic variation, but this provides us with an estimate that part of what determines the disease course of an individual is their genetics.
The second thing that we did is delve into separate genomic regions and really ask, “Are we able to identify a specific region with high statistical confidence that influences the disease course in MS?” We were able to find a region that we were able to then replicate in a separate cohort of people with MS and show that this effect stands and this effect is true. Then, we were able to show also that this same region that is influencing this cross-sectional measure of disability is also influencing longitudinal disability metrics.
To be able to assess the association with susceptibility to MS, we compared the genetic effects on MS susceptibility and severity using genetic correlation across the entire genome. We saw that genetic correlation was low, which means that the genetic influences of susceptibility are not the same as the genetic influences of severity.
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