Exploring the Contribution of Common Genetic Risk Variants to Multiple Sclerosis in Orkney and Shetland: A Study of Unique Populations

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease that affects millions worldwide, with Scotland having one of the highest prevalence rates. In particular, the Orkney Islands hold the distinction of the highest global prevalence of MS, far exceeding the mainland Scotland and even the nearby Shetland Islands. The underlying causes of this elevated prevalence have long puzzled researchers, with both environmental and genetic factors being considered. In this recent study, Barnes et al. (2021) sought to explore the genetic contributions to MS in Orkney and Shetland by analyzing the role of common risk variants and polygenic risk scores (PRS).

A Focus on Population Isolates
Orkney and Shetland are unique due to their population isolates, which makes them particularly intriguing for genetic research. Population isolates typically have reduced genetic diversity compared to larger populations due to their relative geographic and social isolation. This isolation often leads to the accumulation of certain genetic traits, which can be beneficial in identifying links between genetics and diseases such as MS.

Why Look at Common Variants?
Common genetic variants, especially those within the major histocompatibility complex (MHC) region on chromosome 6, are already known to contribute to MS susceptibility. One variant, the HLA-DRB115:01 allele, stands out with an odds ratio (OR) of 2.92, making it a significant risk factor. Barnes et al. aimed to determine whether the high prevalence of MS in Orkney and Shetland could be explained by a higher frequency of such common genetic variants within these isolated populations compared to the mainland Scottish population.

Study Design and Population Samples
The study utilized data from the ORCADES cohort (Orkney), the Viking Health Study (Shetland), and Generation Scotland (mainland Scotland). In total, the study analyzed 97 MS cases and 2,118 controls from Orkney, 15 MS cases and 2,090 controls from Shetland, and 30 MS cases and 8,708 controls from the mainland. These data were used to calculate polygenic risk scores (PRS) based on 127 single nucleotide polymorphisms (SNPs) known to be associated with MS susceptibility.

Polygenic Risk Scores and MS Risk Prediction
The PRS for MS was calculated for each individual in the study, both with and without the inclusion of the HLA-DRB115:01 variant. The results revealed that while MS cases had higher PRS than controls, the common variants alone explained only a small proportion of the MS risk. In fact, the HLA-DRB115:01 variant accounted for most of the genetic risk observed in Orkney and Shetland. The full SNP set used in the study explained approximately 3-5% of the variance in MS risk, aligning with previous estimates from large-scale MS studies.

A Closer Look at Orkney and Shetland
One of the study's key findings was the elevated frequency of the HLA-DRB115:01 variant in Orkney (0.23) and Shetland (0.21), compared to mainland Scotland (0.17). This increased frequency explains a small part of the excess MS prevalence in these islands—9 out of 257 excess cases per 100,000 individuals in Orkney and 6 out of 150 excess cases in Shetland.

However, common variants, including the HLA-DRB115:01 allele, could not fully account for the high rates of MS in Orkney and Shetland. The study suggested that rare genetic variants might play a significant role, especially given the unique genetic makeup of these isolated populations. Additionally, environmental factors, such as obesity—which is prevalent in both Orkney and Shetland—may interact with genetic factors to further elevate MS risk.

Limitations and Future Directions
A notable limitation of the study was its reliance on data from the 2011 International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association study (GWAS). While this dataset provided the most relevant genetic data, it did not include individuals from the Northern Isles, limiting its power. Additionally, the small sample size of MS cases in Orkney and Shetland may have restricted the study's ability to detect more subtle genetic effects.

Future research is likely to focus on identifying rare variants that may be contributing to the excess MS cases in these populations. Whole-genome sequencing may offer new insights, particularly if combined with environmental data to account for gene-environment interactions. As Barnes et al. pointed out, further exploration of the MHC region could also yield valuable information, as it contains other high-risk variants in linkage disequilibrium with the HLA-DRB115:01 allele.

Conclusion
Barnes et al.'s study sheds light on the genetic landscape of MS in Orkney and Shetland, highlighting the role of common risk variants like HLA-DRB115:01. While these variants explain a modest portion of the MS burden in these islands, they do not account for the excess prevalence. The high frequency of the HLA-DRB115:01 allele in Orkney and Shetland may have arisen due to genetic drift, but rare variants and environmental factors likely contribute to the full picture of MS risk in these populations. The study emphasizes the complexity of MS as a disease and the importance of considering both genetic and environmental factors in understanding its causes.

Reference:
Barnes, C.L.K., Hayward, C., Porteous, D.J. et al. Contribution of common risk variants to multiple sclerosis in Orkney and Shetland. Eur J Hum Genet 29, 1701–1709 (2021).