Genome Biology (Jan 2021)

Exploiting the GTEx resources to decipher the mechanisms at GWAS loci

  • Alvaro N. Barbeira,
  • Rodrigo Bonazzola,
  • Eric R. Gamazon,
  • Yanyu Liang,
  • YoSon Park,
  • Sarah Kim-Hellmuth,
  • Gao Wang,
  • Zhuoxun Jiang,
  • Dan Zhou,
  • Farhad Hormozdiari,
  • Boxiang Liu,
  • Abhiram Rao,
  • Andrew R. Hamel,
  • Milton D. Pividori,
  • François Aguet,
  • GTEx GWAS Working Group,
  • Lisa Bastarache,
  • Daniel M. Jordan,
  • Marie Verbanck,
  • Ron Do,
  • GTEx Consortium,
  • Matthew Stephens,
  • Kristin Ardlie,
  • Mark McCarthy,
  • Stephen B. Montgomery,
  • Ayellet V. Segrè,
  • Christopher D. Brown,
  • Tuuli Lappalainen,
  • Xiaoquan Wen,
  • Hae Kyung Im

Journal volume & issue
Vol. 22, no. 1
pp. 1 – 24


Read online

Abstract The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.