Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
By
Alvaro N. Barbeira,
Rodrigo Bonazzola,
Eric R Gamazon,
Yanyu Liang,
YoSon Park,
Sarah Kim-Hellmuth,
Gao Wang,
Zhuoxun Jiang,
Dan Zhou,
Farhad I Hormozdiari,
Boxiang Liu,
Abhiram Rao,
Andrew R. Hamel,
Milton Pividori,
Francois Aguet,
GTEx GWAS Working Group,
Lisa Bastarache,
Daniel M. Jordan,
Marie Verbanck,
Ron Do,
GTEx Consortium,
Matthew Stephens,
Kristen G Ardlie,
Mark McCarthy,
Stephen B. Montgomery,
Ayellet V. Segre,
Christopher D. Brown,
Tuuli Lappalainen,
Xiaoquan Wen,
Hae Kyung Im
Posted 22 Oct 2019
bioRxiv DOI: 10.1101/814350
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 Statement Details of competing interests are listed on the manuscript.
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