Summit: An Integrative Approach for Better Transcriptomic Data Imputation Improves Causal Gene Identification

Authors

Zichen Zhang
Ye Eun Bae
Jonathan R Bradley
Lang Wu
Chong Wu

Publication Date

10-25-2022

Journal

Nature Communications

Abstract

Genes with moderate to low expression heritability may explain a large proportion of complex trait etiology, but such genes cannot be sufficiently captured in conventional transcriptome-wide association studies (TWASs), partly due to the relatively small available reference datasets for developing expression genetic prediction models to capture the moderate to low genetically regulated components of gene expression. Here, we introduce a method, the Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction model accuracy and the power of TWAS by using a large expression quantitative trait loci (eQTL) summary-level dataset. We apply SUMMIT to the eQTL summary-level data provided by the eQTLGen consortium. Through simulation studies and analyses of genome-wide association study summary statistics for 24 complex traits, we show that SUMMIT improves the accuracy of expression prediction in blood, successfully builds expression prediction models for genes with low expression heritability, and achieves higher statistical power than several benchmark methods. Finally, we conduct a case study of COVID-19 severity with SUMMIT and identify 11 likely causal genes associated with COVID-19 severity.

Keywords

Humans, Transcriptome, Genome-Wide Association Study, COVID-19, Quantitative Trait Loci, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease

DOI

10.1038/s41467-022-34016-y

PMID

36284135

PMCID

PMC9593997

PubMedCentral® Posted Date

10-25-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes