Contribution of common risk variants to multiple sclerosis in Orkney and Shetland
Open Access
- 4 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 29 (11), 1701-1709
- https://doi.org/10.1038/s41431-021-00914-w
Abstract
Orkney and Shetland, the population isolates that make up the Northern Isles of Scotland, are of particular interest to multiple sclerosis (MS) research. While MS prevalence is high in Scotland, Orkney has the highest global prevalence, higher than more northerly Shetland. Many hypotheses for the excess of MS cases in Orkney have been investigated, including vitamin D deficiency and homozygosity: neither was found to cause the high prevalence of MS. It is possible that this excess prevalence may be explained through unique genetics. We used polygenic risk scores (PRS) to look at the contribution of common risk variants to MS. Analyses were conducted using ORCADES (97/2118 cases/controls), VIKING (15/2000 cases/controls) and Generation Scotland (30/8708 cases/controls) data sets. However, no evidence of a difference in MS-associated common variant frequencies was found between the three control populations, aside from HLA-DRB1*15:01 tag SNP rs9271069. This SNP had a significantly higher risk allele frequency in Orkney (0.23, p value = 8 × 10–13) and Shetland (0.21, p value = 2.3 × 10–6) than mainland Scotland (0.17). This difference in frequency is estimated to account for 6 (95% CI 3, 8) out of 150 observed excess cases per 100,000 individuals in Shetland and 9 (95% CI 8, 11) of the observed 257 excess cases per 100,000 individuals in Orkney, compared with mainland Scotland. Common variants therefore appear to account for little of the excess burden of MS in the Northern Isles of Scotland.Keywords
This publication has 36 references indexed in Scilit:
- Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA EffectsPLoS Genetics, 2013
- Genome-Wide Association Study of Multiple Sclerosis Confirms a Novel Locus at 5p13.1PLOS ONE, 2012
- Genome-wide homozygosity and multiple sclerosis in Orkney and Shetland IslandersEuropean Journal of Human Genetics, 2011
- Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility lociAnnals of Neurology, 2011
- Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosisNature, 2011
- Genome-wide association study of severity in multiple sclerosisGenes & Immunity, 2011
- Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility lociNature Genetics, 2009
- The Causal Cascade to Multiple Sclerosis: A Model for MS PathogenesisPLOS ONE, 2009
- Runs of Homozygosity in European PopulationsAmerican Journal of Human Genetics, 2008
- Environmental risk factors in multiple sclerosis aetiologyThe Lancet Neurology, 2004