title: Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Institute of Regional Health Research, University of Southern Denmark, Denmark/Hospital of Southern Jutland, Denmark/Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Denmark/ Torshavn National Hospital, Faroe Islands sbinzer@health.sdu.dk.
authors.forename: S
authors.initials: S
authors.lastname: Binzer
authors.affiliation: Institute of Regional Health Research, University of Southern Denmark, Denmark/Hospital of Southern Jutland, Denmark/ MS Clinic of Southern Jutland (Sønderborg, Esbjerg, Vejle), Department of Neurology, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Stenager
authors.affiliation: Institute of Regional Health Research, University of Southern Denmark, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Binzer
authors.affiliation: Department of Clinical Research, University of Southern Denmark, Denmark/Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Denmark.
authors.forename: K O
authors.initials: KO
authors.lastname: Kyvik
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Hillert
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Imrell
mesh_terms: D000328:Adult; D000368:Aged; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D009419:Nerve Tissue Proteins; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface; D018013:Receptors, Neuropeptide / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018013:Receptors, Neuropeptide; C498347:SorCS3 protein, human
keywords: Faroe Islands; Multiple sclerosis; genetics; inbreeding; linkage; risk factors