| Title: | TIPS: a novel pathway-guided joint model for transcriptome-wide association studies |
| Journal: | Briefings in Bioinformatics |
| Published: | 23 Sep 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39550224/ |
| DOI: | https://doi.org/10.1093/bib/bbae587 |
Publication 13654
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Abstract
In the past two decades, genome-wide association studies (GWAS) have pinpointed numerous SNPs linked to human diseases and traits, yet many of these SNPs are in non-coding regions and hard to interpret. Transcriptome-wide association studies (TWAS) integrate GWAS and expression reference panels to identify the associations at gene level with tissue specificity, potentially improving the interpretability. However, the list of individual genes identified from univariate TWAS contains little unifying biological theme, leaving the underlying mechanisms largely elusive. In this paper, we propose a novel multivariate TWAS method that Incorporates Pathway or gene Set information, namely TIPS, to identify genes and pathways most associated with complex polygenic traits. We jointly modeled the imputation and association steps in TWAS, incorporated a sparse group lasso penalty in the model to induce selection at both gene and pathway levels and developed an expectation-maximization algorithm to estimate the parameters for the penalized likelihood. We applied our method to three different complex traits: systolic and diastolic blood pressure, as well as a brain aging biomarker white matter brain age gap in UK Biobank and identified critical biologically relevant pathways and genes associated with these traits. These pathways cannot be detected by traditional univariate TWAS + pathway enrichment analysis approach, showing the power of our model. We also conducted comprehensive simulations with varying heritability levels and genetic architectures and showed our method outperformed other established TWAS methods in feature selection, statistical power, and prediction. The R package that implements TIPS is available at https://github.com/nwang123/TIPS.</p>
8 Keywords
- Algorithms
- Gene Expression Profiling
- Genome-Wide Association Study
- Humans
- Models, Genetic
- Multifactorial Inheritance
- Polymorphism, Single Nucleotide
- Transcriptome
3 Authors
- Neng Wang
- Zhenyao Ye
- Tianzhou Ma
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