MS study of genetic risk factors shows need for diverse data
Many, but not all, risk factors shared across ancestral backgrounds
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- Genetic risk factors for MS are largely shared across diverse ancestries.
- European-focused studies miss unique variants, like one reducing risk in South Asians.
- More diverse genetic research is crucial for a complete understanding of MS.
While many genetic factors that increase the risk of multiple sclerosis (MS) are shared across ancestral backgrounds, a study identified a variant that may reduce MS risk in South Asian people, which had not been seen in European studies — suggesting that studies focusing mainly on people of European descent may miss less common genetic variants in other populations.
“MS genetics has, until now, been overwhelmingly based on people of European ancestry,” Ruth Dobson, PhD, a professor at Queen Mary University of London and the study’s leader, said in a university press release. “This study shows that while many of the biological pathways driving MS are shared, leaving large parts of the global population out of research limits our understanding of the disease. Better representation is not only a fairness issue, it leads to better science.”
The study, “Genetic Determinants of Multiple Sclerosis Susceptibility in People From Diverse Ancestral Backgrounds,” was published in Neurology.
While the exact causes of MS aren’t fully understood, researchers believe the disease develops due to a combination of genetic and environmental factors. To date, more than 200 genetic variants have been shown to contribute to MS risk, yet most studies on genetics have been limited to people of white European ancestry.
Whether the same variants impact the risk of developing the disease in people of other ancestries remains largely unknown.
“MS is likely to be caused by a combination of factors, including lifestyle, environment, and genetics,” said Caitlin Astbury, senior research communications manager at the MS Society U.K. “But almost everything we know about genes and MS comes from studies looking at people of White European descent.”
‘Research like this is vital’
The Queen Mary researchers combined data from the ADAMS project, a registry of ancestrally diverse people with MS from across the U.K., with data from additional patients and controls from the U.K. Biobank.
“Making sure we include people from diverse backgrounds in research is key and the ADAMS study is leading the way,” Astbury said. “Research like this is vital to ensure that progress in MS treatments, diagnosis, and risk prediction benefits everyone.”
The analysis included genetic data from 676 people with MS enrolled in the ADAMS study, and an additional 2,426 patients from the U.K. Biobank. The researchers also analyzed data from 27,640 controls of different ancestries from the U.K. Biobank.
The researchers used genetic ancestry inference to estimate a person’s ancestral background using DNA, and matched patients with controls of the same ancestry to identify genetic variants associated with the disease.
Results showed that genetic variants in the major histocompatibility complex region, which contains genes important for the immune system, were linked to a greater risk of MS across all ancestries.
Other genetic risk factors found in Europeans were also more common in South Asian and African people with MS than in controls of similar ancestry.
However, genetic risk scores, which combine the effects of many DNA variants to estimate disease risk, derived from European populations explained only 3.9% of MS risk in people of South Asian descent and 1.9% in those of African ancestry, compared with 9.6% in Europeans.
This may be partly due to differences in the proportions of people in each population who carry certain genetic variants. For example, HLA-DRB1*15:01, one of the strongest known genetic risk factors in MS, increased MS risk across all groups. But because fewer people of South Asian and African descent carried this variant than Europeans, it explained less of the genetic risk.
The researchers also found a variant in the classical human leukocyte antigen alleles, which are also involved in the immune system, that is relatively common in people of South Asian ancestry and may reduce the risk of MS. This variant, called HLA-A*33:03, had not been previously described because it is rare in people of European ancestry.
“This work demonstrates why diversity matters in genetics,” said Benjamin Jacobs, MD, a clinical lecturer at Queen Mary who worked on the study. “When studies only include one ancestral group, they miss important insights. By broadening participation, we can sharpen our understanding of MS, find risk factors what would otherwise stay hidden and build prediction tools that work for everyone.”
The team said larger studies involving diverse populations “are likely to enhance our understanding of how genetic variation contributes to MS susceptibility in people of all ancestral backgrounds.”
