RT Journal Article
SR Electronic
T1 Widespread dose-dependent effects of RNA expression and splicing on complex diseases and traits
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 814350
DO 10.1101/814350
A1 Alvaro N Barbeira
A1 Rodrigo Bonazzola
A1 Eric R Gamazon
A1 Yanyu Liang
A1 YoSon Park
A1 Sarah Kim-Hellmuth
A1 Gao Wang
A1 Zhuoxun Jiang
A1 Dan Zhou
A1 Farhad Hormozdiari
A1 Boxiang Liu
A1 Abhiram Rao
A1 Andrew R Hamel
A1 Milton D Pividori
A1 François Aguet
A1 GTEx GWAS Working Group
A1 Lisa Bastarache
A1 Daniel M Jordan
A1 Marie Verbanck
A1 Ron Do
A1 GTEx Consortium
A1 Matthew Stephens
A1 Kristin Ardlie
A1 Mark McCarthy
A1 Stephen B Montgomery
A1 Ayellet V Segrè
A1 Christopher D. Brown
A1 Tuuli Lappalainen
A1 Xiaoquan Wen
A1 Hae Kyung Im
YR 2019
UL http://biorxiv.org/content/early/2019/10/22/814350.abstract
AB The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human traits and diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genetic loci discovered by genome-wide association studies (GWAS). Across a broad set of complex traits and diseases, we find widespread dose-dependent effects of RNA expression and splicing, with higher impact on molecular phenotypes translating into higher impact downstream. Using colocalization and association approaches that take into account the observed allelic heterogeneity, 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.