Multi-INTACT: integrative analysis of the genome, transcriptome, and proteome identifies causal mechanisms of complex traits

Genome Biol. 2025 Feb 3;26(1):19. doi: 10.1186/s13059-025-03480-2.

Abstract

We present multi-integration of transcriptome-wide association studies and colocalization (Multi-INTACT), an algorithm that models multiple "gene products" (e.g., encoded RNA transcript and protein levels) to implicate causal genes and relevant gene products. In simulations, Multi-INTACT achieves higher power than existing methods, maintains calibrated false discovery rates, and detects the true causal gene product(s). We apply Multi-INTACT to GWAS on 1408 metabolites, integrating the GTEx expression and UK Biobank protein QTL datasets. Multi-INTACT infers 52 to 109% more metabolite causal genes than protein-alone or expression-alone analyses and indicates both gene products are relevant for most gene nominations.

MeSH terms

  • Algorithms
  • Gene Expression Profiling
  • Genome-Wide Association Study
  • Humans
  • Multifactorial Inheritance*
  • Proteome* / genetics
  • Quantitative Trait Loci
  • Transcriptome*

Substances

  • Proteome