title: A genome-wide association study in progressive multiple sclerosis.
abstract: BACKGROUND
  The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established.
  
  
  OBJECTIVE
  We aimed to identify genetic variants associated with progressive MS (PrMS).
  
  
  METHODS
  We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10(-4)) in two independent sets of primary progressive MS cases and controls.
  
  
  RESULTS
  We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934(T), p                 (combined)=6.7×10(-16), OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343(G), p                 (combined)=2.4×10(-5), OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a 'cis' effect on RNA expression in lymphoblastic cell lines, but pathway analyses of 'trans' effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02).
  
  
  CONCLUSIONS
  We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.
authors.affiliation: Institute of Experimental Neurology and Department of Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy. martinelli.filippo@hsr.it
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli-Boneschi
authors.forename: Federica
authors.initials: F
authors.lastname: Esposito
authors.forename: Paola
authors.initials: P
authors.lastname: Brambilla
authors.forename: Eva
authors.initials: E
authors.lastname: Lindström
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lavorgna
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.forename: Mariaemma
authors.initials: M
authors.lastname: Rodegher
authors.forename: Ruggero
authors.initials: R
authors.lastname: Capra
authors.forename: Angelo
authors.initials: A
authors.lastname: Ghezzi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coniglio
authors.forename: Bruno
authors.initials: B
authors.lastname: Colombo
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.forename: David
authors.initials: D
authors.lastname: Booth
authors.forename: Annette Bang
authors.initials: AB
authors.lastname: Oturai
authors.forename: Graeme
authors.initials: G
authors.lastname: Stewart
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
authors.forename: Trevor John
authors.initials: TJ
authors.lastname: Kilpatrick
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.forename: Hadi
authors.initials: H
authors.lastname: Abderrahim
authors.forename: Jerome
authors.initials: J
authors.lastname: Wojcik
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
mesh_terms: D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D006680:HLA Antigens