Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor.
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.
Ban
Maria
M
Department of Clinical Neuroscience, Addenbrooke's, Hospital, University of Cambridge, Cambridge, UK. mb531@medschl.cam.ac.uk
Goris
An
A
Lorentzen
Aslaug R
AR
Baker
Amie
A
Mihalova
Tania
T
Ingram
Gillian
G
Booth
David R
DR
Heard
Robert N
RN
Stewart
Graeme J
GJ
Bogaert
Elke
E
Dubois
Bénédicte
B
Harbo
Hanne F
HF
Celius
Elisabeth G
EG
Spurkland
Anne
A
Strange
Richard
R
Hawkins
Clive
C
Robertson
Neil P
NP
Dudbridge
Frank
F
Wason
James
J
De Jager
Philip L
PL
Hafler
David
D
Rioux
John D
JD
Ivinson
Adrian J
AJ
McCauley
Jacob L
JL
Pericak-Vance
Margaret
M
Oksenberg
Jorge R
JR
Hauser
Stephen L
SL
Sexton
David
D
Haines
Jonathan
J
Sawcer
Stephen
S
Compston
Alastair
A
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*
D053634:TYK2 Kinase; C070139:TYK2 protein, human