Simultaneous detection of novel genes and SNPs by adaptive p-value combination
Combining SNP p-values from GWAS summary data is a promising strategy for detecting novel genetic factors. Existing statistical methods for the p-value-based SNP-set testing confront two challenges. First, the statistical power of different methods depends on unknown patterns of genetic effects that...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.1009428/full |
| _version_ | 1811312292582653952 |
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| author | Xiaohui Chen Hong Zhang Ming Liu Hong-Wen Deng Zheyang Wu Zheyang Wu |
| author_facet | Xiaohui Chen Hong Zhang Ming Liu Hong-Wen Deng Zheyang Wu Zheyang Wu |
| author_sort | Xiaohui Chen |
| collection | DOAJ |
| description | Combining SNP p-values from GWAS summary data is a promising strategy for detecting novel genetic factors. Existing statistical methods for the p-value-based SNP-set testing confront two challenges. First, the statistical power of different methods depends on unknown patterns of genetic effects that could drastically vary over different SNP sets. Second, they do not identify which SNPs primarily contribute to the global association of the whole set. We propose a new signal-adaptive analysis pipeline to address these challenges using the omnibus thresholding Fisher’s method (oTFisher). The oTFisher remains robustly powerful over various patterns of genetic effects. Its adaptive thresholding can be applied to estimate important SNPs contributing to the overall significance of the given SNP set. We develop efficient calculation algorithms to control the type I error rate, which accounts for the linkage disequilibrium among SNPs. Extensive simulations show that the oTFisher has robustly high power and provides a higher balanced accuracy in screening SNPs than the traditional Bonferroni and FDR procedures. We applied the oTFisher to study the genetic association of genes and haplotype blocks of the bone density-related traits using the summary data of the Genetic Factors for Osteoporosis Consortium. The oTFisher identified more novel and literature-reported genetic factors than existing p-value combination methods. Relevant computation has been implemented into the R package TFisher to support similar data analysis. |
| first_indexed | 2024-04-13T10:33:49Z |
| format | Article |
| id | doaj.art-52d3539a85a54d7688ba3acdf0bbb0b4 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-13T10:33:49Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-52d3539a85a54d7688ba3acdf0bbb0b42022-12-22T02:50:06ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-11-011310.3389/fgene.2022.10094281009428Simultaneous detection of novel genes and SNPs by adaptive p-value combinationXiaohui Chen0Hong Zhang1Ming Liu2Hong-Wen Deng3Zheyang Wu4Zheyang Wu5Department of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, MA, United StatesTranslational Biomarker Statistics, Global Biometrics and Data Management, Pfizer Inc., Cambridge, MA, United StatesBioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA, United StatesDivision of Biomedical Informatics & Genomics, School of Medicine, Tulane University, New Orleans, LA, United StatesDepartment of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, MA, United StatesBioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA, United StatesCombining SNP p-values from GWAS summary data is a promising strategy for detecting novel genetic factors. Existing statistical methods for the p-value-based SNP-set testing confront two challenges. First, the statistical power of different methods depends on unknown patterns of genetic effects that could drastically vary over different SNP sets. Second, they do not identify which SNPs primarily contribute to the global association of the whole set. We propose a new signal-adaptive analysis pipeline to address these challenges using the omnibus thresholding Fisher’s method (oTFisher). The oTFisher remains robustly powerful over various patterns of genetic effects. Its adaptive thresholding can be applied to estimate important SNPs contributing to the overall significance of the given SNP set. We develop efficient calculation algorithms to control the type I error rate, which accounts for the linkage disequilibrium among SNPs. Extensive simulations show that the oTFisher has robustly high power and provides a higher balanced accuracy in screening SNPs than the traditional Bonferroni and FDR procedures. We applied the oTFisher to study the genetic association of genes and haplotype blocks of the bone density-related traits using the summary data of the Genetic Factors for Osteoporosis Consortium. The oTFisher identified more novel and literature-reported genetic factors than existing p-value combination methods. Relevant computation has been implemented into the R package TFisher to support similar data analysis.https://www.frontiersin.org/articles/10.3389/fgene.2022.1009428/fullGWAS summary statisticsSNP-set analysisp-value combinationFisher’s methodglobal hypothesis testosteoporosis |
| spellingShingle | Xiaohui Chen Hong Zhang Ming Liu Hong-Wen Deng Zheyang Wu Zheyang Wu Simultaneous detection of novel genes and SNPs by adaptive p-value combination Frontiers in Genetics GWAS summary statistics SNP-set analysis p-value combination Fisher’s method global hypothesis test osteoporosis |
| title | Simultaneous detection of novel genes and SNPs by adaptive p-value combination |
| title_full | Simultaneous detection of novel genes and SNPs by adaptive p-value combination |
| title_fullStr | Simultaneous detection of novel genes and SNPs by adaptive p-value combination |
| title_full_unstemmed | Simultaneous detection of novel genes and SNPs by adaptive p-value combination |
| title_short | Simultaneous detection of novel genes and SNPs by adaptive p-value combination |
| title_sort | simultaneous detection of novel genes and snps by adaptive p value combination |
| topic | GWAS summary statistics SNP-set analysis p-value combination Fisher’s method global hypothesis test osteoporosis |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.1009428/full |
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