Contribution of common risk variants to multiple sclerosis in Orkney and Shetland

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.

Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation

“…Moreover, four higher-risk women and one lower-risk woman had T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria 31 for dissemination in space as well as other MRI features associated with MS, supporting the presence of a higher risk of developing MS in individuals with higher genetic burden and environmental risks. In a recent study, a weighted sum score calculation using 127 common risk variants from the IMSGC study (2011) and GWAS Catalogue was performed in singleton MS cases and controls from Orkney and Shetland populations 32 . It was shown that MS cases had significantly higher sum scores compared with the controls in each population, although there were no apparent differences among the three control populations, suggesting that the high MS prevalence in the Northern Isles of Scotland cannot be attributed to these common variants.…”

Polygenic risk scores for autoimmune related diseases are significantly different and skewed in cancer exceptional responders

“…The general mathematical formula of the PRS is written as follows: where X i denotes the effect allele count and w i denotes the weight of the i-th SNP for a specified outcome. The number of SNPs included in PRS varies, depending on the trait/disease and were determined in the earlier studies[9,22,23] (see Supplementary Table 2). When comparing PRSs between NEER and PCAWG, only variants shared between the two cohorts were included.…”

“…We implemented several previously published PRSs models corresponding to several autoimmune/inflammatory disorders, including type 1 diabetes (T1D) [22], rheumatoid arthritis (RA) [18], psoriasis [18], multiple sclerosis (MS) [23], inflammatory bowel disease (IBD) [19] and hypothyroidism [9]. The ERs showed significantly higher PRS scores for hypothyroidism, T1D and Psoriasis risk.…”

Polygenic risk scores for autoimmune related diseases are significantly different and skewed in cancer exceptional responders

“…We implemented several previously published PRS models corresponding to several autoimmune disorders, including type 1 diabetes (T1D) [5], rheumatoid arthritis (RA)[6], psoriasis[6], MS [7], in ammatory bowel disease (IBD)[8], hypothyroidism [2], and celiac disease[6]. The ERs showed signi cantly higher PRSs for hypothyroidism, T1D and Psoriasis risk.…”