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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2021

Open Access 01-12-2021 | Research

Integrative eQTL-weighted hierarchical Cox models for SNP-set based time-to-event association studies

Authors: Haojie Lu, Yongyue Wei, Zhou Jiang, Jinhui Zhang, Ting Wang, Shuiping Huang, Ping Zeng

Published in: Journal of Translational Medicine | Issue 1/2021

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Abstract

Background

Integrating functional annotations into SNP-set association studies has been proven a powerful analysis strategy. Statistical methods for such integration have been developed for continuous and binary phenotypes; however, the SNP-set integrative approaches for time-to-event or survival outcomes are lacking.

Methods

We here propose IEHC, an integrative eQTL (expression quantitative trait loci) hierarchical Cox regression, for SNP-set based survival association analysis by modeling effect sizes of genetic variants as a function of eQTL via a hierarchical manner. Three p-values combination tests are developed to examine the joint effects of eQTL and genetic variants after a novel decorrelated modification of statistics for the two components. An omnibus test (IEHC-ACAT) is further adapted to aggregate the strengths of all available tests.

Results

Simulations demonstrated that the IEHC joint tests were more powerful if both eQTL and genetic variants contributed to association signal, while IEHC-ACAT was robust and often outperformed other approaches across various simulation scenarios. When applying IEHC to ten TCGA cancers by incorporating eQTL from relevant tissues of GTEx, we revealed that substantial correlations existed between the two types of effect sizes of genetic variants from TCGA and GTEx, and identified 21 (9 unique) cancer-associated genes which would otherwise be missed by approaches not incorporating eQTL.

Conclusion

IEHC represents a flexible, robust, and powerful approach to integrate functional omics information to enhance the power of identifying association signals for the survival risk of complex human cancers.
Appendix
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Metadata
Title
Integrative eQTL-weighted hierarchical Cox models for SNP-set based time-to-event association studies
Authors
Haojie Lu
Yongyue Wei
Zhou Jiang
Jinhui Zhang
Ting Wang
Shuiping Huang
Ping Zeng
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-021-03090-z

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