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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

Graph illustrating genes located in proximity to SNPs rs1327328 and rs7326018 on chromosome 13.SNP rs1327328 was the second most significant SNP validated in the Spanish and US replication cohorts, and is in strong linkage disequilibrium with SNP rs7326018. SNPs rs1330943, rs9588771, rs6492466, rs9583760, rs4284505, and rs9589207 have been typed by HapMap.
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pone-0003490-g002: Graph illustrating genes located in proximity to SNPs rs1327328 and rs7326018 on chromosome 13.SNP rs1327328 was the second most significant SNP validated in the Spanish and US replication cohorts, and is in strong linkage disequilibrium with SNP rs7326018. SNPs rs1330943, rs9588771, rs6492466, rs9583760, rs4284505, and rs9589207 have been typed by HapMap.

Mentions: As mentioned above, SNPs rs1327328 and rs7326018 lie in a position of chromosome 13 devoid of any known functional elements. As shown in Figure 2, the region were these SNPs are located contains several genes (ENSG00000184837, ENSG00000165618 and LOC121727) and microRNAs (hsa-mir-622, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-20a and hsa-mir-19b-1). Within or close to some of these functional elements, there are SNPs that have been typed by HapMap. Linkage disequilibrium analysis between SNPs rs1327328 and rs7326018 and the SNPs mapping in the functional elements is summarized in Table 6. Linkage disequilibrium measures are highly significant between SNPs rs1327328 and rs7326018 and SNP rs4284505, located next to a cluster of microRNAs, and marginally significant with SNP rs9583760, located within LOC121727 (similar to Peroxisome assembly protein 12 (Peroxin-12) (Peroxisome assembly factor 3) (PAF-3)).


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)

Graph illustrating genes located in proximity to SNPs rs1327328 and rs7326018 on chromosome 13.SNP rs1327328 was the second most significant SNP validated in the Spanish and US replication cohorts, and is in strong linkage disequilibrium with SNP rs7326018. SNPs rs1330943, rs9588771, rs6492466, rs9583760, rs4284505, and rs9589207 have been typed by HapMap.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003490-g002: Graph illustrating genes located in proximity to SNPs rs1327328 and rs7326018 on chromosome 13.SNP rs1327328 was the second most significant SNP validated in the Spanish and US replication cohorts, and is in strong linkage disequilibrium with SNP rs7326018. SNPs rs1330943, rs9588771, rs6492466, rs9583760, rs4284505, and rs9589207 have been typed by HapMap.
Mentions: As mentioned above, SNPs rs1327328 and rs7326018 lie in a position of chromosome 13 devoid of any known functional elements. As shown in Figure 2, the region were these SNPs are located contains several genes (ENSG00000184837, ENSG00000165618 and LOC121727) and microRNAs (hsa-mir-622, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-20a and hsa-mir-19b-1). Within or close to some of these functional elements, there are SNPs that have been typed by HapMap. Linkage disequilibrium analysis between SNPs rs1327328 and rs7326018 and the SNPs mapping in the functional elements is summarized in Table 6. Linkage disequilibrium measures are highly significant between SNPs rs1327328 and rs7326018 and SNP rs4284505, located next to a cluster of microRNAs, and marginally significant with SNP rs9583760, located within LOC121727 (similar to Peroxisome assembly protein 12 (Peroxin-12) (Peroxisome assembly factor 3) (PAF-3)).

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