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Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis.

ABSTRACT: Genome-wide association studies (GWAS), although efficient to detect genes involved in complex diseases, are not designed to measure the real effect of the genes. This is illustrated here by the example of IL2RA in multiple sclerosis (MS). Association between IL2RA and MS is clearly established, although the functional variation is still unknown: the effect of IL2RA might be better described by several SNPs than by a single one. This study investigates whether a pair of SNPs better explains the observed linkage and association data than a single SNP. In total, 522 trio families and 244 affected sib-pairs were typed for 26 IL2RA SNPs. For each SNP and pairs of SNPs, the phased genotypes of patients and controls were compared to determine the SNP set offering the best risk discrimination. Consistency between the genotype risks provided by the retained set and the identical by descent allele sharing in affected sib-pairs was assessed. After controlling for multiple testing, the set of SNPs rs2256774 and rs3118470, provides the best discrimination between the case and control genotype distributions (P-corrected=0.009). The relative risk between the least and most at-risk genotypes is 3.54 with a 95% confidence interval of [2.14-5.94]. Furthermore, the linkage information provided by the allele sharing between affected sibs is consistent with the retained set (P=0.80) but rejects the SNP reported in the literature (P=0.006). Establishing a valid modeling of a disease gene is essential to test its potential interaction with other genes and to reconstruct the pathophysiological pathways.

SUBMITTER: Babron MC

PROVIDER: S-EPMC3283173 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis.

Babron Marie-Claude MC Perdry Hervé H Handel Adam E AE Ramagopalan Sreeram V SV Damotte Vincent V Fontaine Bertrand B Müller-Myhsok Bertram B Ebers George C GC Clerget-Darpoux Françoise F

European journal of human genetics : EJHG 20111116 3

Genome-wide association studies (GWAS), although efficient to detect genes involved in complex diseases, are not designed to measure the real effect of the genes. This is illustrated here by the example of IL2RA in multiple sclerosis (MS). Association between IL2RA and MS is clearly established, although the functional variation is still unknown: the effect of IL2RA might be better described by several SNPs than by a single one. This study investigates whether a pair of SNPs better explains the ...[more]

PMID: 22085902

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Project description:ObjectivesTo analyze the tissue heterogeneity of hormone-sensitive and drug-resistant nephrotic syndrome genes using a bioinformatics approach and to analyze gene-related functional pathways.MethodsThe limma package of R software was used to screen differential genes from the nephropathy datasets GSE145969 and GSE189734. The differential genes were analyzed for functional and pathway enrichment in terms of biological processes, cellular components, and molecular functions. The Metascape tool was used to construct protein networks for the differential genes, and the results were imported into Cytoscape software for visualization. The genes were identified as key modules and genes using the MCODE plug-in. Gene set enrichment analysis was performed for the HALLMARK analysis of the two microarray key genes to obtain the relevant pathways.ResultsGSE145969 screened 351 differential genes, 168 upregulated genes, and 183 downregulated genes. The differential genes were enriched in biological processes, cellular components, and molecular functions, such as myocardial contraction, intracellular nonmembrane organelles, and structural molecular activities. The protein-protein interaction (PPI) network contained 140 nodes, with the highest-scoring module containing seven genes, and the MCODE plug-in calculated the downseed. The key gene was KIAA0101, whose HALLMARK pathway was significantly enriched in the mTORC1 signaling pathway. A total of 263 differential genes were screened by GSE189734, and they were enriched in biological processes, molecular functions, and cellular components, such as immune system processes, signaling receptor binding, and the cytoplasmic matrix. The PPI network contained 253 nodes, with the highest-scoring module containing 37 genes. The seed gene obtained through the MCODE plug-in calculation was IL2RA, whose HALLMARK pathway was significantly enriched in the KRAS signaling pathway.ConclusionBy analyzing the gene sets of different tissues in nephropathy, two key genes, namely KIAA0101 and IL2RA, were obtained. Their gene function enrichment is related to cell growth, development, and reproduction. Therefore, IL2RA and KIAA0101 can be used as diagnostic markers for hormone-resistant nephropathy.

Dataset Information

Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis.

Publications

Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis.

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