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Exploiting SNP correlations within random forest for genome-wide association studies.

ABSTRACT: The primary goal of genome-wide association studies (GWAS) is to discover variants that could lead, in isolation or in combination, to a particular trait or disease. Standard approaches to GWAS, however, are usually based on univariate hypothesis tests and therefore can account neither for correlations due to linkage disequilibrium nor for combinations of several markers. To discover and leverage such potential multivariate interactions, we propose in this work an extension of the Random Forest algorithm tailored for structured GWAS data. In terms of risk prediction, we show empirically on several GWAS datasets that the proposed T-Trees method significantly outperforms both the original Random Forest algorithm and standard linear models, thereby suggesting the actual existence of multivariate non-linear effects due to the combinations of several SNPs. We also demonstrate that variable importances as derived from our method can help identify relevant loci. Finally, we highlight the strong impact that quality control procedures may have, both in terms of predictive power and loci identification. Variable importance results and T-Trees source code are all available at www.montefiore.ulg.ac.be/~botta/ttrees/ and github.com/0asa/TTree-source respectively.

SUBMITTER: Botta V

PROVIDER: S-EPMC3973686 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Exploiting SNP correlations within random forest for genome-wide association studies.

Botta Vincent V Louppe Gilles G Geurts Pierre P Wehenkel Louis L

PloS one 20140402 4

The primary goal of genome-wide association studies (GWAS) is to discover variants that could lead, in isolation or in combination, to a particular trait or disease. Standard approaches to GWAS, however, are usually based on univariate hypothesis tests and therefore can account neither for correlations due to linkage disequilibrium nor for combinations of several markers. To discover and leverage such potential multivariate interactions, we propose in this work an extension of the Random Forest ...[more]

PMID: 24695491

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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:BACKGROUND: Recently we have witnessed a surge of interest in using genome-wide association studies (GWAS) to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs), have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs. RESULTS: We describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1) for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one) SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2) ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one from European-American (EA) and the other from African-American (AA). In the EA data set, we found 22 pathways with nominal P-value less than or equal to 0.001 and corresponding false discovery rate (FDR) less than 5%. In the AA data set, we found 11 pathways by controlling the same nominal P-value and FDR threshold. Interestingly, 8 of these pathways overlap with those found in the EA sample. We have implemented our method in a JAVA software package, called SNP Set Enrichment Analysis (SSEA), which contains a user-friendly interface and is freely available at http://cbcl.ics.uci.edu/SSEA. CONCLUSIONS: The SNP-based pathway enrichment method described here offers a new alternative approach for analysing GWAS data. By applying it to schizophrenia GWAS studies, we show that our method is able to identify statistically significant pathways, and importantly, pathways that can be replicated in large genetically distinct samples.

Dataset Information

Exploiting SNP correlations within random forest for genome-wide association studies.

Publications

Exploiting SNP correlations within random forest for genome-wide association studies.

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