Influence of tissue context on gene prioritization for predicted transcriptome-wide association studies

摘要

Transcriptome-wide association studies (TWAS) have recently gained great attention due to their ability to prioritize complex trait-associated genes and promote potential therapeutics development for complex human diseases. TWAS integrates genotypic data with expression quantitative trait loci (eQTLs) to predict genetically regulated gene expression components and associates predictions with a trait of interest. As such, TWAS can prioritize genes whose differential expressions contribute to the trait of interest and provide mechanistic explanation of complex trait(s). Tissue-specific eQTL information grants TWAS the ability to perform association analysis on tissues whose gene expression profiles are otherwise hard to obtain, such as liver and heart. However, as eQTLs are tissue context-dependent, whether and how the tissue-specificity of eQTLs influences TWAS gene prioritization has not been fully investigated. In this study, we addressed this question by adopting two distinct TWAS methods, PrediXcan and UTMOST, which assume single tissue and integrative tissue effects of eQTLs, respectively. Thirty-eight baseline laboratory traits in 4,360 antiretroviral treatment-na?ve individuals from the AIDS Clinical Trials Group (ACTG) studies comprised the input dataset for TWAS. We performed TWAS in a tissue-specific manner and obtained a total of 430 significant gene-trait associations (q-value < 0.05) across multiple tissues. Single tissue-based analysis by PrediXcan contributed 116 of the 430 associations including 64 unique gene-trait pairs in 28 tissues. Integrative tissue-based analysis by UTMOST found the other 314 significant associations that include 50 unique gene-trait pairs across all 44 tissues. Both analyses were able to replicate some associations identified in past variant-based genome-wide association studies (GWAS), such as high-density lipoprotein (HDL) and CETP (PrediXcan, q-value = 3.2e-16). Both analyses also identified novel associations. Moreover, si