Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians.
A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.
Rubio
J P
JP
The Howard Florey Institute, Melbourne, Victoria, Australia. justin.rubio@florey.edu.au
Stankovich
J
J
Field
J
J
Tubridy
N
N
Marriott
M
M
Chapman
C
C
Bahlo
M
M
Perera
D
D
Johnson
L J
LJ
Tait
B D
BD
Varney
M D
MD
Speed
T P
TP
Taylor
B V
BV
Foote
S J
SJ
Butzkueven
H
H
Kilpatrick
T J
TJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D001315:Australia; D018968:CD58 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012269:Ribosomal Proteins / Q000235:genetics*
D018968:CD58 Antigens; C522505:CLEC16A protein, human; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins; D012269:Ribosomal Proteins; C029742:ribosomal protein L5