TY - JOUR
T1 - An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability
AU - Li, Lei
AU - Huang, Kai-Lieh
AU - Gao, Yipeng
AU - Cui, Ya
AU - Wang, Gao
AU - Elrod, Nathan
AU - Li, Yumei
AU - Chen, Yiling Elaine
AU - Ji, Ping
AU - Peng, Fanglue
AU - Russell, William K.
AU - Wagner, Eric
AU - Li, Wei
N1 - Funding Information:
We thank L. Hou, Z. Cui and members of the Li laboratory for helpful discussions. This work was supported by a Computational Cancer Biology Training Program fellowship Cancer Prevention Research Institute of Texas (CPRIT) grant no. RP170593 (K.-L.H.), National Institutes of Health grants to W.L. (nos. R01HG007538, R01CA193466, R01CA228140), P.J. (no. R03CA223893), E.J.W. (no. R01GM134539) and a University of California, Irvine (UCI) Cancer Center support grant (no. P30CA062203). E.J.W. acknowledges support from University of Texas Medical Branch (UTMB) Department of Biochemistry and Molecular Biology startup funds and the Welch Foundation (no. H-1889). The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant no. RP190682 (W.K.R.). We also thank I. Toufique and P. Papadopoulos at the UCI Research Cyber Infrastructure Center for high-performance computing support.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/7
Y1 - 2021/7
N2 - Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3′UTR alternative polyadenylation (APA) quantitative trait loci (3′aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project). Mechanistically, 3′aQTLs can alter poly(A) motifs, RNA secondary structure and RNA-binding protein–binding sites, leading to thousands of APA changes. Our CRISPR-based experiments indicate that such 3′aQTLs can alter APA regulation. Furthermore, we demonstrate that mapping 3′aQTLs can identify APA regulators, such as La-related protein 4. Finally, 3′aQTLs are colocalized with approximately 16.1% of trait-associated variants and are largely distinct from other QTLs, such as expression QTLs. Together, our findings show that 3′aQTLs contribute substantially to the molecular mechanisms underlying human complex traits and diseases.
AB - Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3′UTR alternative polyadenylation (APA) quantitative trait loci (3′aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project). Mechanistically, 3′aQTLs can alter poly(A) motifs, RNA secondary structure and RNA-binding protein–binding sites, leading to thousands of APA changes. Our CRISPR-based experiments indicate that such 3′aQTLs can alter APA regulation. Furthermore, we demonstrate that mapping 3′aQTLs can identify APA regulators, such as La-related protein 4. Finally, 3′aQTLs are colocalized with approximately 16.1% of trait-associated variants and are largely distinct from other QTLs, such as expression QTLs. Together, our findings show that 3′aQTLs contribute substantially to the molecular mechanisms underlying human complex traits and diseases.
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U2 - 10.1038/s41588-021-00864-5
DO - 10.1038/s41588-021-00864-5
M3 - Article
C2 - 33986536
AN - SCOPUS:85105778598
SN - 1061-4036
VL - 53
SP - 994
EP - 1005
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -