Examination of seven candidate regions for multiple sclerosis: strong evidence of linkage to chromosome 1q44

Kenealy, Shannon J.; Herrel, L. A.; Bradford, Yuki; Schnetz-Boutaud, Nathalie; Oksenberg, Jorge R.; Barcellos, Lisa F.; Schmidt, Silke; Gregory, Simon G.; Pericak‐Vance, Margaret A.; Haines, Jonathan L.

doi:10.1038/sj.gene.6364275

Cited by 15 publications

(14 citation statements)

References 28 publications

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“…Molecular mechanisms leading to migration of autoreactive T cells from the bloodstream involve a series of sequential and overlapping interactions among different families of adhesion molecules, including selectins [2]. The selectin gene cluster maps to chromosome 1q23-25, close to regions previously associated with MS [3,4]. This information supports the notion that the selectin gene cluster is a good positional and functional candidate for MS. Several variants have been described in selectin genes.…”

supporting

confidence: 59%

Candidate gene analysis of selectin cluster in patients with multiple sclerosis

et al. 2009

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Three single nucleotide polymorphisms (SNPs) with a potential impact on the function of selectins (rs6133, rs4987310 and rs5368 substitutions localized in the coding regions of P-sel, L-sel and E-sel, respectively) were analyzed in an Italian population of 165 patients with multiple sclerosis (MS) as compared with 149 controls and in a replication American population of Caucasian descent consisting of 122 patients and 50 controls. No significant differences in either allelic or genotypic frequency in all the SNPs tested were found in the Italian population. A tendency to an increased frequency of the rs6133 T allele was observed in the American population, but applying the Bonferroni correction the significance threshold was not reached. Haploview analysis demonstrated that rs4987310 and rs5368 markers are in strong LD (D' = 0.97) in both populations. Combining the two SNPs, we found no difference in haplotype distribution in patients compared with controls, either in Italian or in American population. Despite the fact that selectins play a role in the pathogenesis of MS and their encoding genes are located in regions associated with the disease, the selectin gene cluster studied likely does not influence the susceptibility to MS in Caucasians.

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supporting

confidence: 59%

Candidate gene analysis of selectin cluster in patients with multiple sclerosis

et al. 2009

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“…We analyzed SNPs in a ~ 7.0-Mb region of human 1q43 that showed suggestive linkage to multiple sclerosis (MS) [15,16]. This region was bounded by SNPs rs10925296 and rs1319790 (encompassing chr1:233,515,650-240,494,277 of human Build 35).…”

Section: Resultsmentioning

confidence: 99%

“…We have formulated a systematic approach to prioritize SNP markers to be genotyped for association studies in any target region, with a specific application to the 1q43 linkage region in MS [15,16]. This approach incorporates MCS analysis to prioritize markers within MCSs, termed MCS-SNPs, for high-throughput genotyping.…”

Section: Introductionmentioning

confidence: 99%

SNPs in Multi-Species Conserved Sequences (MCS) as useful markers in association studies: a practical approach

et al. 2007

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Background: Although genes play a key role in many complex diseases, the specific genes involved in most complex diseases remain largely unidentified. Their discovery will hinge on the identification of key sequence variants that are conclusively associated with disease. While much attention has been focused on variants in protein-coding DNA, variants in noncoding regions may also play many important roles in complex disease by altering gene regulation. Since the vast majority of noncoding genomic sequence is of unknown function, this increases the challenge of identifying "functional" variants that cause disease. However, evolutionary conservation can be used as a guide to indicate regions of noncoding or coding DNA that are likely to have biological function, and thus may be more likely to harbor SNP variants with functional consequences. To help bias marker selection in favor of such variants, we devised a process that prioritizes annotated SNPs for genotyping studies based on their location within Multi-species Conserved Sequences (MCSs) and used this process to select SNPs in a region of linkage to a complex disease. This allowed us to evaluate the utility of the chosen SNPs for further association studies. Previously, a region of chromosome 1q43 was linked to Multiple Sclerosis (MS) in a genome-wide screen. We chose annotated SNPs in the region based on location within MCSs (termed MCS-SNPs). We then obtained genotypes for 478 MCS-SNPs in 989 individuals from MS families.

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“…A combined genomic map of MS was constructed using 170 microsatellite markers or regions previously reported in whole genome linkage screens 2-14 and their follow-up studies, [20][21][22][23][24][25] and 263 'top-ranked' markers reported in the case-control association studies of the GAMES project. 15 These markers or regions were selected based on the statistics reported in the original studies, including both significant and suggested occurrences.…”

Section: Resultsmentioning

confidence: 99%

Mapping candidate non-MHC susceptibility regions to multiple sclerosis

et al. 2006

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Understanding the genetic basis of multiple sclerosis (MS) remains a major challenge, despite decades of intensive research. In order to identify candidate non-MHC susceptibility regions to MS, the results of whole genome screens for linkage or association and follow-up studies in 18 different populations were superimposed together in a combined genomic map. Analysis of this map led to the prediction of at least 38 potential susceptibility regions, each showing linkage and/or association in several populations. Among these, 17 regions were the most reproducibly reported in these studies, thus representing top predicted candidates for MS. This non-formal approach to meta-analysis demonstrated the ability to verify results and retrieve lost information in an association study. Assessment of the map in a Northern Irish refined screen (n ¼ 415 cases, n ¼ 490 controls) revealed association in 15 regions (Po0.05), including 10 promising candidates on chromosomes 1p13, 2p13, 2q14, 3p23, 7q21, 13q14, 15q13, 17p13, 18q21 and 20p12 (Po0.0025). Seven of these regions were previously overlooked in the Northern Irish whole genome association study. Collating results from numerous studies, this draft map represents a tool that should facilitate the analysis of the genetic backgrounds of MS in many populations.

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Examination of seven candidate regions for multiple sclerosis: strong evidence of linkage to chromosome 1q44

Cited by 15 publications

References 28 publications

Candidate gene analysis of selectin cluster in patients with multiple sclerosis

Candidate gene analysis of selectin cluster in patients with multiple sclerosis

SNPs in Multi-Species Conserved Sequences (MCS) as useful markers in association studies: a practical approach

Mapping candidate non-MHC susceptibility regions to multiple sclerosis

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