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The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study.

ABSTRACT: In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin.We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19 × 10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35 × 10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19 × 10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios).Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.

SUBMITTER: International Multiple Sclerosis Genetics Consortium

PROVIDER: S-EPMC3084233 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study.

PloS one 20110428 4

<h4>Background</h4>In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin.<h4>Principal findings</h4>We calculated individual and ...[more]

PMID: 21552549

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Project description:ObjectiveMultiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome-wide association studies have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple- and single-case families.MethodsA weighted log-additive integrative approach termed MS genetic burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1,213 independent MS families (810 sporadic and 403 multicase families).ResultsMSGB analysis demonstrated a higher aggregation of susceptibility variants in multicase compared to sporadic MS families. In addition, the aggregation of non-major histocompatibility complex single nucleotide polymorphisms depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, although a greater MSGB in siblings of MS patients was associated with an increased risk of MS (odds ratio, 2.1; p = 0.001), receiver operating characteristic curves of MSGB differences between probands and sibs (area under the receiver operator curves, 0.57 [95% confidence interval, 0.53-0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data.InterpretationThe primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis on assembling large case-control datasets, multigenerational, multiaffected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits.

Dataset Information

The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study.

Publications

The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study.

Similar Datasets

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