Exploiting the GTEx resources to decipher the mechanisms at GWAS loci.

Autor: Barbeira AN; Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA., Bonazzola R; Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA., Gamazon ER; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Data Science Institute, Vanderbilt University, Nashville, TN, USA.; Clare Hall, University of Cambridge, Cambridge, UK.; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Liang Y; Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA., Park Y; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Kim-Hellmuth S; Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.; New York Genome Center, New York, NY, USA.; Department of Systems Biology, Columbia University, New York, NY, USA., Wang G; Department of Human Genetics, University of Chicago, Chicago, IL, USA., Jiang Z; Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA., Zhou D; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Hormozdiari F; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Liu B; Department of Biology, Stanford University, Stanford, 94305, CA, USA., Rao A; Department of Biology, Stanford University, Stanford, 94305, CA, USA., Hamel AR; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA., Pividori MD; Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA., Aguet F; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bastarache L; Department of Biomedical Informatics, Department of Medicine, Vanderbilt University, Nashville, TN, USA.; Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA., Jordan DM; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Verbanck M; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Université de Paris - EA 7537 BIOSTM, Paris, France., Do R; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Stephens M; Department of Human Genetics, University of Chicago, Chicago, IL, USA., Ardlie K; The Broad Institute of MIT and Harvard, Cambridge, MA, USA., McCarthy M; University of Oxford, Oxford, UK., Montgomery SB; Department of Genetics, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Segrè AV; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA., Brown CD; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Lappalainen T; New York Genome Center, New York, NY, USA.; Department of Systems Biology, Columbia University, New York, NY, USA., Wen X; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA., Im HK; Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA. haky@uchicago.edu.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2021 Jan 26; Vol. 22 (1), pp. 49. Date of Electronic Publication: 2021 Jan 26.
DOI: 10.1186/s13059-020-02252-4
Abstrakt: 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.
Databáze: MEDLINE