Journal article
A tissue-specific collaborative mixed model for jointly analyzing multiple tissues in transcriptome-wide association studies
Nucleic acids research, Vol.48(19), pp.e109-e109
11/04/2020
DOI: 10.1093/nar/gkaa767
PMCID: PMC7641735
PMID: 32978944
Abstract
AbstractTranscriptome-wide association studies (TWASs) integrate expression quantitative trait loci (eQTLs) studies with genome-wide association studies (GWASs) to prioritize candidate target genes for complex traits. Several statistical methods have been recently proposed to improve the performance of TWASs in gene prioritization by integrating the expression regulatory information imputed from multiple tissues, and made significant achievements in improving the ability to detect gene-trait associations. Unfortunately, most existing multi-tissue methods focus on prioritization of candidate genes, and cannot directly infer the specific functional effects of candidate genes across different tissues. Here, we propose a tissue-specific collaborative mixed model (TisCoMM) for TWASs, leveraging the co-regulation of genetic variations across different tissues explicitly via a unified probabilistic model. TisCoMM not only performs hypothesis testing to prioritize gene-trait associations, but also detects the tissue-specific role of candidate target genes in complex traits. To make full use of widely available GWASs summary statistics, we extend TisCoMM to use summary-level data, namely, TisCoMM-S2. Using extensive simulation studies, we show that type I error is controlled at the nominal level, the statistical power of identifying associated genes is greatly improved, and the false-positive rate (FPR) for non-causal tissues is well controlled at decent levels. We further illustrate the benefits of our methods in applications to summary-level GWASs data of 33 complex traits. Notably, apart from better identifying potential trait-associated genes, we can elucidate the tissue-specific role of candidate target genes. The follow-up pathway analysis from tissue-specific genes for asthma shows that the immune system plays an essential function for asthma development in both thyroid and lung tissues.
Details
- Title: Subtitle
- A tissue-specific collaborative mixed model for jointly analyzing multiple tissues in transcriptome-wide association studies
- Creators
- Xingjie Shi - Nanjing University of Finance and EconomicsXiaoran Chai - Peking UniversityYi Yang - National University of SingaporeQing Cheng - National University of SingaporeYuling Jiao - Wuhan UniversityHaoyue Chen - Zhejiang UniversityJian Huang - University of IowaCan Yang - Hong Kong University of Science and TechnologyJin Liu - National University of Singapore
- Resource Type
- Journal article
- Publication Details
- Nucleic acids research, Vol.48(19), pp.e109-e109
- DOI
- 10.1093/nar/gkaa767
- PMID
- 32978944
- PMCID
- PMC7641735
- ISSN
- 0305-1048
- eISSN
- 1362-4962
- Grant note
- DOI: 10.13039/100016017, name: Duke-NUS Medical School, award: R-913-200-098-263, MOE2016-T2-2-029, MOE2018-T2-1-046, MOE2018-T2-2-006; DOI: 10.13039/501100001459, name: Ministry of Education - Singapore, award: 11871474, 61701547; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China; name: Hong Kong Research Grant Council, award: 12301417, 16307818, 16301419, DMS-1916199; DOI: 10.13039/100000001, name: National Science Foundation
- Language
- English
- Date published
- 11/04/2020
- Academic Unit
- Statistics and Actuarial Science
- Record Identifier
- 9984257627202771
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