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Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms.

Comabella M, Craig DW, Camiña-Tato M, Morcillo C, Lopez C, Navarro A, Rio J, BiomarkerMS Study GroupMontalban X, Martin R - PLoS ONE (2008)

Bottom Line: The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation.The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy.The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility.

View Article: PubMed Central - PubMed

Affiliation: Unitat de Neuroimmunologia Clínica, CEM-Cat, Hospital Universitari Vall d'Hebron, Barcelona, Spain. mcomabel@ir.vhebron.net

ABSTRACT
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease.

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Related in: MedlinePlus

Graphs showing physical position of SNP rs3129934 on chromosome 6.SNP rs3129934, which showed the strongest association with the disease in the Spanish and US replication cohorts, is located approximately 200 kb from the HLA-DRB1 locus.
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pone-0003490-g001: Graphs showing physical position of SNP rs3129934 on chromosome 6.SNP rs3129934, which showed the strongest association with the disease in the Spanish and US replication cohorts, is located approximately 200 kb from the HLA-DRB1 locus.

Mentions: Our GWA study design and the pooling-based strategy is essentially validated by the fact that the single most significant SNP neighbors the HLA-DRB/DQA loci. Specifically, rs3129934 is approximately 200 kb from the HLA-DRB1 locus (Figure 1) and has a p-value of 1.4×10−5 with an OR of 3 (Table 2). Previous studies have identified linkage disequilibrium between HLA haplotypes and tagSNPs within the MHC [11]. Based on these data, rs3129934 is in very high linkage disequilibrium with SNP rs3135388 and demonstrated to tag the HLA-DRB associated haplotype in MS (D′ = 0.964 R2 = 0.93). The extremely strong linkage disequilibrium between these two markers allows us to conclude that the association of rs3129934 results from the HLA-DRB1 locus and that the association observed with rs3129934 does not represent a second MHC association signal.


Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms.

Comabella M, Craig DW, Camiña-Tato M, Morcillo C, Lopez C, Navarro A, Rio J, BiomarkerMS Study GroupMontalban X, Martin R - PLoS ONE (2008)

Graphs showing physical position of SNP rs3129934 on chromosome 6.SNP rs3129934, which showed the strongest association with the disease in the Spanish and US replication cohorts, is located approximately 200 kb from the HLA-DRB1 locus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2566815&req=5

pone-0003490-g001: Graphs showing physical position of SNP rs3129934 on chromosome 6.SNP rs3129934, which showed the strongest association with the disease in the Spanish and US replication cohorts, is located approximately 200 kb from the HLA-DRB1 locus.
Mentions: Our GWA study design and the pooling-based strategy is essentially validated by the fact that the single most significant SNP neighbors the HLA-DRB/DQA loci. Specifically, rs3129934 is approximately 200 kb from the HLA-DRB1 locus (Figure 1) and has a p-value of 1.4×10−5 with an OR of 3 (Table 2). Previous studies have identified linkage disequilibrium between HLA haplotypes and tagSNPs within the MHC [11]. Based on these data, rs3129934 is in very high linkage disequilibrium with SNP rs3135388 and demonstrated to tag the HLA-DRB associated haplotype in MS (D′ = 0.964 R2 = 0.93). The extremely strong linkage disequilibrium between these two markers allows us to conclude that the association of rs3129934 results from the HLA-DRB1 locus and that the association observed with rs3129934 does not represent a second MHC association signal.

Bottom Line: The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation.The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy.The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility.

View Article: PubMed Central - PubMed

Affiliation: Unitat de Neuroimmunologia Clínica, CEM-Cat, Hospital Universitari Vall d'Hebron, Barcelona, Spain. mcomabel@ir.vhebron.net

ABSTRACT
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease.

Show MeSH
Related in: MedlinePlus