Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians

Abstract

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 ¼ 0.001, IL2RA (rs2104286) P ¼ 0.033, RPL5 (rs6604026) P ¼ 0.041 and CD58 (rs12044852) P ¼ 0.042. There was no association (P ¼ 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 ¼ 3 Â 10 À8 ) evidence of an association between KIAA0350 and risk of disease.

RGMA and IL21R show association with experimental inflammation and multiple sclerosis

“…5,6 Only recently, with analysis of very large cohorts, non-human leukocyte antigen MS genes are starting to be unambiguously identified. [7][8][9][10][11][12][13][14] Another important concept is the sharing of risk genes between inflammatory diseases, 15 as now demonstrated for type 1 diabetes and MS genes. 12 Therefore, cross-disciplinary genetics may be rewarding.…”

Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus

“…All were included in the study as part of the tagging SNP set, except rs6498169, previously reported to be associated with MS and anti-CCP-negative rheumatoid arthritis. 2,6,8,11 The most significantly associated SNP, rs12923849 has previously showed some degree of association with T1D. 1 The other three top hits in our screening phase; rs9934231, rs6498168 and rs7206912 have not previously been reported to be associated in MS or other autoimmune diseases.…”

“…[1][2][3] Multiple replication and candidate gene studies have verified this region as being disease associated in T1D and MS, and association with CLEC16A has also been found in anti-cyclic citrullinated peptide (CCP) negative rheumatoid arthritis, juvenile idiopathic arthritis, Addison's disease and NOD2-negative Crohn's disease. [4][5][6][7][8][9] The association of CLEC16A SNPs across multiple immune-mediated diseases and the observation that the gene is almost uniquely expressed on immune cells, make a common effect on autoimmunity likely. The CLEC16A protein belongs to the C-type lectin family whose immune functions include differentiation of self versus non-self glycoproteins and the induction of the appropriate immune response.…”

“…2 This SNP association has been replicated and confirmed at genomewide significance level in MS (Po5 Â 10 À7 ). 6,11 In T1D, the strongest association so far has been found for four SNPs situated in intron 19 and 22; rs12708716, 9 rs725613, rs2903692 and rs17673553, 1 which are all in fairly strong linkage disequilibrium (LD) (r 2 ¼ 0.66-1.00; haploview v 4.1, hapmap release 21, CEU sample set (Utah residents with Northern and Western European ancestry from the Centre de'Etude du Polymorphism Human (CEPH) collection). 12,13 The LD between the MSassociated rs6498169 and the T1D SNPs is modest (r 2 ¼ 0.18-0.26), 12,13 and association with rs6498169 has not been found in T1D.…”

Where is the causal variant? On the advantage of the family design over the case–control design in genetic association studies

“…Several studies find association between MS and this gene in Caucasian populations. [8][9][10][11][12][13] The method using case-control data selects a minimal subset of seven associated SNPs, which reduces to three SNPs when using family data. The second step shows that none of these SNPs is causal, and that the association signal is due to at least two different ungenotyped variants in the region.…”