PT  - JOURNAL ARTICLE
AU  - Alvaro N Barbeira
AU  - Rodrigo Bonazzola
AU  - Eric R Gamazon
AU  - Yanyu Liang
AU  - YoSon Park
AU  - Sarah Kim-Hellmuth
AU  - Gao Wang
AU  - Zhuoxun Jiang
AU  - Dan Zhou
AU  - Farhad Hormozdiari
AU  - Boxiang Liu
AU  - Abhiram Rao
AU  - Andrew R Hamel
AU  - Milton D Pividori
AU  - François Aguet
AU  - GTEx GWAS Working Group
AU  - Lisa Bastarache
AU  - Daniel M Jordan
AU  - Marie Verbanck
AU  - Ron Do
AU  - GTEx Consortium
AU  - Matthew Stephens
AU  - Kristin Ardlie
AU  - Mark McCarthy
AU  - Stephen B Montgomery
AU  - Ayellet V Segrè
AU  - Christopher D. Brown
AU  - Tuuli Lappalainen
AU  - Xiaoquan Wen
AU  - Hae Kyung Im
TI  - Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
AID  - 10.1101/814350
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 814350
4099  - http://biorxiv.org/content/early/2020/05/23/814350.short
4100  - http://biorxiv.org/content/early/2020/05/23/814350.full
AB  - 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% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.Competing Interest StatementDetails of competing interests are listed on the manuscript.