title: Combinations of susceptibility genes are associated with higher risk for multiple sclerosis and imply disease course specificity.
abstract: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by a genome wide association study (GWAS) conducted by the International Multiple Sclerosis Genetic Consortium in a multinational cohort prompting the discovery of 57 non-MHC MS-associated common genetic variants. Hitherto, few of these newly reported variants have been replicated in larger independent patient cohorts. We genotyped a cohort of 1033 MS patients and 644 healthy controls with a consistent genetic background for the 57 non-MHC variants reported to be associated with MS by the first large GWAS as well as the HLA DRB1*1501 tagging SNP rs3135388. We robustly replicated three of the 57 non-MHC reported MS-associated single nucleotide polymorphisms (SNPs). In addition, our study revealed several genotype-genotype combinations with an evidently higher degree of disease association than the genotypes of the single SNPs. We further correlated well-defined clinical phenotypes, i.e. ataxia, visual impairment due to optic neuritis and paresis with single SNPs and genotype combinations, and identified several associations. The results may open new avenues for clinical implications of the MS associated genetic variants reported from large GWAS.
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Olischewsky
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Reiner
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hellwig
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Sarika
authors.initials: S
authors.lastname: Esser
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Epplen
authors.affiliation: Faculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Tomaz
authors.initials: T
authors.lastname: Curk
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Aiden
authors.initials: A
authors.lastname: Haghikia
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D012307:Risk Factors; D014786:Vision Disorders / Q000235:genetics