An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
30
01
2020
accepted:
05
04
2021
pubmed:
15
5
2021
medline:
31
8
2021
entrez:
14
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33986536
doi: 10.1038/s41588-021-00864-5
pii: 10.1038/s41588-021-00864-5
doi:
Substances chimiques
3' Untranslated Regions
0
RNA, Messenger
0
Poly A
24937-83-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
994-1005Subventions
Organisme : NCI NIH HHS
ID : R01 CA193466
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA223893
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG007538
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM134539
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228140
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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