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
Affiliations
- Alvaro N. Barbeira
- Section of Genetic Medicine, Department of Medicine, The University of Chicago
- Rodrigo Bonazzola
- Section of Genetic Medicine, Department of Medicine, The University of Chicago
- Eric R. Gamazon
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center
- Yanyu Liang
- Section of Genetic Medicine, Department of Medicine, The University of Chicago
- YoSon Park
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine
- Sarah Kim-Hellmuth
- Statistical Genetics, Max Planck Institute of Psychiatry
- Gao Wang
- Department of Human Genetics, University of Chicago
- Zhuoxun Jiang
- Section of Genetic Medicine, Department of Medicine, The University of Chicago
- Dan Zhou
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center
- Farhad Hormozdiari
- The Broad Institute of MIT and Harvard
- Boxiang Liu
- Department of Biology, Stanford University
- Abhiram Rao
- Department of Biology, Stanford University
- Andrew R. Hamel
- The Broad Institute of MIT and Harvard
- Milton D. Pividori
- Section of Genetic Medicine, Department of Medicine, The University of Chicago
- François Aguet
- The Broad Institute of MIT and Harvard
- GTEx GWAS Working Group
- Lisa Bastarache
- Department of Biomedical Informatics, Department of Medicine, Vanderbilt University
- Daniel M. Jordan
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- Marie Verbanck
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- Ron Do
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- GTEx Consortium
- Matthew Stephens
- Department of Human Genetics, University of Chicago
- Kristin Ardlie
- The Broad Institute of MIT and Harvard
- Mark McCarthy
- University of Oxford
- Stephen B. Montgomery
- Department of Genetics, Stanford University
- Ayellet V. Segrè
- The Broad Institute of MIT and Harvard
- Christopher D. Brown
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine
- Tuuli Lappalainen
- New York Genome Center
- Xiaoquan Wen
- Department of Biostatistics, University of Michigan
- Hae Kyung Im
- Section of Genetic Medicine, Department of Medicine, The University of Chicago
- DOI
- https://doi.org/10.1186/s13059-020-02252-4
- Journal volume & issue
-
Vol. 22,
no. 1
pp. 1 – 24
Abstract
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.
