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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-03826-2 |
| _version_ | 1818842097337237504 |
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| 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 |
| collection | DOAJ |
| 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 . |
| first_indexed | 2024-12-19T04:36:33Z |
| format | Article |
| id | doaj.art-fcd910eb80374dde9d35755bc772fbc6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:36:33Z |
| publishDate | 2017-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-fcd910eb80374dde9d35755bc772fbc62022-12-21T20:35:44ZengNature PortfolioScientific Reports2045-23222017-06-01711810.1038/s41598-017-03826-2Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocksHuiying Zhao0Dale R. Nyholt1Yuanhao Yang2Jihua Wang3Yuedong Yang4Institute of Health and Biomedical Innovation, Queensland University of TechnologyInstitute of Health and Biomedical Innovation, Queensland University of TechnologyInstitute of Health and Biomedical Innovation, Queensland University of TechnologyShandong Provincial Key Laboratory of Functional Macromolecular Biophysics, Dezhou UniversityInstitute for Glycomics, Griffith University, Parkland DrAbstract 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 .https://doi.org/10.1038/s41598-017-03826-2 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-017-03826-2 |
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