| Title: | Conditional transcriptome-wide association study for fine-mapping candidate causal genes |
| Journal: | Nature Genetics |
| Published: | 26 Jan 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38279040/ |
| DOI: | https://doi.org/10.1038/s41588-023-01645-y |
Publication 8861
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Abstract
Transcriptome-wide association studies (TWASs) aim to integrate genome-wide association studies with expression-mapping studies to identify genes with genetically predicted expression (GReX) associated with a complex trait. In the present report, we develop a method, GIFT (gene-based integrative fine-mapping through conditional TWAS), that performs conditional TWAS analysis by explicitly controlling for GReX of all other genes residing in a local region to fine-map putatively causal genes. GIFT is frequentist in nature, explicitly models both expression correlation and cis-single nucleotide polymorphism linkage disequilibrium across multiple genes and uses a likelihood framework to account for expression prediction uncertainty. As a result, GIFT produces calibrated P values and is effective for fine-mapping. We apply GIFT to analyze six traits in the UK Biobank, where GIFT narrows down the set size of putatively causal genes by 32.16-91.32% compared with existing TWAS fine-mapping approaches. The genes identified by GIFT highlight the importance of vessel regulation in determining blood pressures and lipid metabolism for regulating lipid levels.</p>
8 Authors
- Lu Liu
- Ran Yan
- Ping Guo
- Jiadong Ji
- Weiming Gong
- Fuzhong Xue
- Zhongshang Yuan
- Xiang Zhou
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