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An efficient weighted tag SNP-set analytical method in genome-wide association studies.

ABSTRACT: Single-nucleotide polymorphism (SNP)-set analysis in Genome-wide association studies (GWAS) has emerged as a research hotspot for identifying genetic variants associated with disease susceptibility. But most existing methods of SNP-set analysis are affected by the quality of SNP-set, and poor quality of SNP-set can lead to low power in GWAS.In this research, we propose an efficient weighted tag-SNP-set analytical method to detect the disease associations. In our method, we first design a fast algorithm to select a subset of SNPs (called tag SNP-set) from a given original SNP-set based on the linkage disequilibrium (LD) between SNPs, then assign a proper weight to each of the selected tag SNP respectively and test the joint effect of these weighted tag SNPs. The intensive simulation results show that the power of weighted tag SNP-set-based test is much higher than that of weighted original SNP-set-based test and that of un-weighted tag SNP-set-based test. We also compare the powers of the weighted tag SNP-set-based test based on four types of tag SNP-sets. The simulation results indicate the method of selecting tag SNP-set impacts the power greatly and the power of our proposed method is the highest.From the analysis of simulated replicated data sets, we came to a conclusion that weighted tag SNP-set-based test is a powerful SNP-set test in GWAS. We also designed a faster algorithm of selecting tag SNPs which include most of information of original SNP-set, and a better weighted function which can describe the status of each tag SNP in GWAS.

SUBMITTER: Yan B

PROVIDER: S-EPMC4373116 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An efficient weighted tag SNP-set analytical method in genome-wide association studies.

Yan Bin B Wang Shudong S Jia Huaqian H Liu Xing X Wang Xinzeng X

BMC genetics 20150313

<h4>Background</h4>Single-nucleotide polymorphism (SNP)-set analysis in Genome-wide association studies (GWAS) has emerged as a research hotspot for identifying genetic variants associated with disease susceptibility. But most existing methods of SNP-set analysis are affected by the quality of SNP-set, and poor quality of SNP-set can lead to low power in GWAS.<h4>Results</h4>In this research, we propose an efficient weighted tag-SNP-set analytical method to detect the disease associations. In ou ...[more]

PMID: 25879733

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Project description:BackgroundThe typical objective of Genome-wide association (GWA) studies is to identify single-nucleotide polymorphisms (SNPs) and corresponding genes with the strongest evidence of association (the 'most-significant SNPs/genes' approach). Borrowing ideas from micro-array data analysis, we propose a new method, named RS-SNP, for detecting sets of genes enriched in SNPs moderately associated to the phenotype. RS-SNP assesses whether the number of significant SNPs, with p-value P ? ?, belonging to a given SNP set S is statistically significant. The rationale of proposed method is that two kinds of null hypotheses are taken into account simultaneously. In the first null model the genotype and the phenotype are assumed to be independent random variables and the null distribution is the probability of the number of significant SNPs in S greater than observed by chance. The second null model assumes the number of significant SNPs in S depends on the size of and not on the identity of the SNPs in . Statistical significance is assessed using non-parametric permutation tests.ResultsWe applied RS-SNP to the Crohn's disease (CD) data set collected by the Wellcome Trust Case Control Consortium (WTCCC) and compared the results with GENGEN, an approach recently proposed in literature. The enrichment analysis using RS-SNP and the set of pathways contained in the MSigDB C2 CP pathway collection highlighted 86 pathways rich in SNPs weakly associated to CD. Of these, 47 were also indicated to be significant by GENGEN. Similar results were obtained using the MSigDB C5 pathway collection. Many of the pathways found to be enriched by RS-SNP have a well-known connection to CD and often with inflammatory diseases.ConclusionsThe proposed method is a valuable alternative to other techniques for enrichment analysis of SNP sets. It is well founded from a theoretical and statistical perspective. Moreover, the experimental comparison with GENGEN highlights that it is more robust with respect to false positive findings.

Project description:A typical genome-wide association study (GWAS) analyzes millions of single-nucleotide polymorphisms (SNPs), several of which are in a region of the same gene. To conduct gene set analysis (GSA), information from SNPs needs to be unified at the gene level. A widely used practice is to use only the most relevant SNP per gene; however, there are other methods of integration that could be applied here. Also, the problem of nonrandom association of alleles at two or more loci is often neglected. Here, we tested the impact of incorporation of different integrations and linkage disequilibrium (LD) correction on the performance of several GSA methods. Matched normal and breast cancer samples from The Cancer Genome Atlas database were used to evaluate the performance of six GSA algorithms: Coincident Extreme Ranks in Numerical Observations (CERNO), Gene Set Enrichment Analysis (GSEA), GSEA-SNP, improved GSEA for GWAS (i-GSEA4GWAS), Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA), and Over-Representation Analysis (ORA). Association of SNPs to phenotype was calculated using modified McNemar's test. Results for SNPs mapped to the same gene were integrated using Fisher and Stouffer methods and compared with the minimum p-value method. Four common measures were used to quantify the performance of all combinations of methods. Results of GSA analysis on GWAS were compared to the one performed on gene expression data. Comparing all evaluation metrics across different GSA algorithms, integrations, and LD correction, we highlighted CERNO, and MAGENTA with Stouffer as the most efficient. Applying LD correction increased prioritization and specificity of enrichment outcomes for all tested algorithms. When Fisher or Stouffer were used with LD, sensitivity and reproducibility were also better. Using any integration method was beneficial in comparison with a minimum p-value method in specific combinations. The correlation between GSA results from genomic and transcriptomic level was the highest when Stouffer integration was combined with LD correction. We thoroughly evaluated different approaches to GSA in GWAS in terms of performance to guide others to select the most effective combinations. We showed that LD correction and Stouffer integration could increase the performance of enrichment analysis and encourage the usage of these techniques.

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An efficient weighted tag SNP-set analytical method in genome-wide association studies.

Publications

An efficient weighted tag SNP-set analytical method in genome-wide association studies.

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