Identify gene targets and cell-type specificity of non-coding GWAS variants

Determine the target genes regulated by trait-associated non-coding genetic variants identified by genome-wide association studies and ascertain the specific human cell types in which these regulatory effects on gene expression occur, to clarify variant-to-gene and tissue-specific regulatory mechanisms in complex diseases.

Background

A major challenge highlighted in the paper is that most trait-associated variants identified by GWAS lie in non-coding regions and are presumed to act through regulatory effects on gene expression. However, pinpointing the downstream gene targets and the tissue or cell-type contexts of these regulatory effects remains unresolved. This uncertainty limits mechanistic interpretation of GWAS findings for complex diseases such as coronary artery disease.

The authors present a network-driven TWAS framework that incorporates both cis- and trans-regulatory effects via tissue-specific gene regulatory networks to improve identification of gene-disease associations. Addressing the open problem of mapping variant-to-gene and cell-type-specific regulation is central to validating and extending such integrative approaches.