title: Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor.
abstract: In a recent genome-wide association study (GWAS) based on 12,374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 x 10(-6), odds ratio=1.32 (1.17-1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis.
authors.affiliation: Department of Clinical Neuroscience, Addenbrooke's, Hospital, University of Cambridge, Cambridge, UK. mb531@medschl.cam.ac.uk
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.forename: Aslaug R
authors.initials: AR
authors.lastname: Lorentzen
authors.forename: Amie
authors.initials: A
authors.lastname: Baker
authors.forename: Tania
authors.initials: T
authors.lastname: Mihalova
authors.forename: Gillian
authors.initials: G
authors.lastname: Ingram
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
authors.forename: Robert N
authors.initials: RN
authors.lastname: Heard
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: Elke
authors.initials: E
authors.lastname: Bogaert
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dubois
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Celius
authors.forename: Anne
authors.initials: A
authors.lastname: Spurkland
authors.forename: Richard
authors.initials: R
authors.lastname: Strange
authors.forename: Clive
authors.initials: C
authors.lastname: Hawkins
authors.forename: Neil P
authors.initials: NP
authors.lastname: Robertson
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.forename: James
authors.initials: J
authors.lastname: Wason
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: David
authors.initials: D
authors.lastname: Hafler
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Ivinson
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.forename: Margaret
authors.initials: M
authors.lastname: Pericak-Vance
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: David
authors.initials: D
authors.lastname: Sexton
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haines
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
mesh_terms: D000328:Adult; D000483:Alleles; D005192:Family Health; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D053634:TYK2 Kinase / Q000235:genetics*
chemical_list: D053634:TYK2 Kinase; C070139:TYK2 protein, human