Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene.

BACKGROUND: In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. OBJECTIVE: The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands. METHODS: Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program. RESULTS: A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008). CONCLUSION: This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.

High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis.

BACKGROUND: Large population-based genome-wide association studies have identified several multiple sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies. Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded conflicting results. OBJECTIVES: In this study we investigated the role of consanguinity on MS risk in the relatively isolated Faroe Islands, which have a presumed high level of inbreeding. METHODS: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients, number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes as measures of relatedness. Parametric and non-parametric statistical models were applied. RESULTS: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding coefficients, large number of observed homozygotes and many long ROH. However, apart from the number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed. CONCLUSIONS: Overall, no significant difference between cases and controls were found, indicating that consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe Islands.

Multiple sclerosis in a family on the Faroe Islands.

BACKGROUND: John Kurtzke has proposed that multiple sclerosis (MS) on the Faroe Islands occurred as a result of the spread of a transmittable agent brought to the country during World War II. AIM: Kurtzke's theory has been opposed earlier and in this study, we present a family from the Faroe Islands containing a total of 14 family members with MS which show further inconsistencies with the theory. The present study is to our knowledge, the first description of familial incidences of MS on the Faroe Islands. METHODS: Medical histories were gathered from 12 family members and 6 of the 8 living MS cases were human leukocyte antigen (HLA)-typed. RESULTS: Seven family members had primary progressive MS (PPMS), while five had relapsing remitting MS. The HLA-DR15 allele was carried by the three cases with the most aggressive form of MS and they shared a common haplotypes. The HLA types carried by the remaining cases varied. CONCLUSION: This research questions Kurtzke's theory as three of the cases do not conform to the epidemic cohorts described. Furthermore, there appears to be a higher than usual prevalence of PPMS. The high degree of heterogeneity of the HLA types carried indicates that HLA alleles do not independently explain the risk of developing MS.