Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.
We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.
De Jager
Philip L
PL
Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. pdejager@rics.bwh.harvard.edu
Jia
Xiaoming
X
Wang
Joanne
J
de Bakker
Paul I W
PI
Ottoboni
Linda
L
Aggarwal
Neelum T
NT
Piccio
Laura
L
Raychaudhuri
Soumya
S
Tran
Dong
D
Aubin
Cristin
C
Briskin
Rebeccah
R
Romano
Susan
S
Baranzini
Sergio E
SE
McCauley
Jacob L
JL
Pericak-Vance
Margaret A
MA
Haines
Jonathan L
JL
Gibson
Rachel A
RA
Naeglin
Yvonne
Y
Uitdehaag
Bernard
B
Matthews
Paul M
PM
Kappos
Ludwig
L
Polman
Chris
C
McArdle
Wendy L
WL
Strachan
David P
DP
Evans
Denis
D
Cross
Anne H
AH
Daly
Mark J
MJ
Compston
Alastair
A
Sawcer
Stephen J
SJ
Weiner
Howard L
HL
Hauser
Stephen L
SL
Hafler
David A
DA
Oksenberg
Jorge R
JR
D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D050835:Interferon Regulatory Factors; D047888:Receptors, Tumor Necrosis Factor, Type I; D000099185:Interferon Regulatory Factor-8; C062279:CD6 antigen; C506235:TNFRSF1A protein, human