Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks

Abstract Genome-wide association studies (GWAS) have successfully identified single variants associated with diseases. To increase the power of GWAS, gene-based and pathway-based tests are commonly employed to detect more risk factors. However, the gene- and pathway-based association tests may be bi...

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Autores principales:	Huiying Zhao, Dale R. Nyholt, Yuanhao Yang, Jihua Wang, Yuedong Yang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fcd910eb80374dde9d35755bc772fbc6
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spelling	oai:doaj.org-article:fcd910eb80374dde9d35755bc772fbc62021-12-02T11:51:13ZImproving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks10.1038/s41598-017-03826-22045-2322https://doaj.org/article/fcd910eb80374dde9d35755bc772fbc62017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03826-2https://doaj.org/toc/2045-2322Abstract Genome-wide association studies (GWAS) have successfully identified single variants associated with diseases. To increase the power of GWAS, gene-based and pathway-based tests are commonly employed to detect more risk factors. However, the gene- and pathway-based association tests may be biased towards genes or pathways containing a large number of single-nucleotide polymorphisms (SNPs) with small P-values caused by high linkage disequilibrium (LD) correlations. To address such bias, numerous pathway-based methods have been developed. Here we propose a novel method, DGAT-path, to divide all SNPs assigned to genes in each pathway into LD blocks, and to sum the chi-square statistics of LD blocks for assessing the significance of the pathway by permutation tests. The method was proven robust with the type I error rate >1.6 times lower than other methods. Meanwhile, the method displays a higher power and is not biased by the pathway size. The applications to the GWAS summary statistics for schizophrenia and breast cancer indicate that the detected top pathways contain more genes close to associated SNPs than other methods. As a result, the method identified 17 and 12 significant pathways containing 20 and 21 novel associated genes, respectively for two diseases. The method is available online by http://sparks-lab.org/server/DGAT-path .Huiying ZhaoDale R. NyholtYuanhao YangJihua WangYuedong YangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Huiying Zhao Dale R. Nyholt Yuanhao Yang Jihua Wang Yuedong Yang Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks
description	Abstract Genome-wide association studies (GWAS) have successfully identified single variants associated with diseases. To increase the power of GWAS, gene-based and pathway-based tests are commonly employed to detect more risk factors. However, the gene- and pathway-based association tests may be biased towards genes or pathways containing a large number of single-nucleotide polymorphisms (SNPs) with small P-values caused by high linkage disequilibrium (LD) correlations. To address such bias, numerous pathway-based methods have been developed. Here we propose a novel method, DGAT-path, to divide all SNPs assigned to genes in each pathway into LD blocks, and to sum the chi-square statistics of LD blocks for assessing the significance of the pathway by permutation tests. The method was proven robust with the type I error rate >1.6 times lower than other methods. Meanwhile, the method displays a higher power and is not biased by the pathway size. The applications to the GWAS summary statistics for schizophrenia and breast cancer indicate that the detected top pathways contain more genes close to associated SNPs than other methods. As a result, the method identified 17 and 12 significant pathways containing 20 and 21 novel associated genes, respectively for two diseases. The method is available online by http://sparks-lab.org/server/DGAT-path .
format	article
author	Huiying Zhao Dale R. Nyholt Yuanhao Yang Jihua Wang Yuedong Yang
author_facet	Huiying Zhao Dale R. Nyholt Yuanhao Yang Jihua Wang Yuedong Yang
author_sort	Huiying Zhao
title	Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks
title_short	Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks
title_full	Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks
title_fullStr	Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks
title_full_unstemmed	Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks
title_sort	improving the detection of pathways in genome-wide association studies by combined effects of snps from linkage disequilibrium blocks
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/fcd910eb80374dde9d35755bc772fbc6
work_keys_str_mv	AT huiyingzhao improvingthedetectionofpathwaysingenomewideassociationstudiesbycombinedeffectsofsnpsfromlinkagedisequilibriumblocks AT dalernyholt improvingthedetectionofpathwaysingenomewideassociationstudiesbycombinedeffectsofsnpsfromlinkagedisequilibriumblocks AT yuanhaoyang improvingthedetectionofpathwaysingenomewideassociationstudiesbycombinedeffectsofsnpsfromlinkagedisequilibriumblocks AT jihuawang improvingthedetectionofpathwaysingenomewideassociationstudiesbycombinedeffectsofsnpsfromlinkagedisequilibriumblocks AT yuedongyang improvingthedetectionofpathwaysingenomewideassociationstudiesbycombinedeffectsofsnpsfromlinkagedisequilibriumblocks
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Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks

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