Exploiting the GTEx resources to decipher the mechanisms at GWAS loci.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
26 01 2021
26 01 2021
Historique:
received:
06
06
2020
accepted:
18
12
2020
entrez:
27
1
2021
pubmed:
28
1
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33499903
doi: 10.1186/s13059-020-02252-4
pii: 10.1186/s13059-020-02252-4
pmc: PMC7836161
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
49Subventions
Organisme : NIMH NIH HHS
ID : R01 MH101814
Pays : United States
Organisme : National Institute of Diabetes and Digestive and Kidney Diseases (US)
ID : P30DK20595
Organisme : NHGRI NIH HHS
ID : U01 HG007598
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007824
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM138121
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101822
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133218
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG009494
Pays : United States
Organisme : National Institute of Health
ID : R01MH107666
Organisme : NHGRI NIH HHS
ID : R35 HG010718
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG011138
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007593
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000430
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124836
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139865
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG055477
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201000029C
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133559
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY031424
Pays : United States
Références
Circ Genom Precis Med. 2019 May;12(5):e002376
pubmed: 30939045
Cell. 2011 Sep 30;147(1):32-43
pubmed: 21962505
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
pubmed: 15608251
Nat Genet. 2015 Sep;47(9):1091-8
pubmed: 26258848
Xenobiotica. 2008 Jul;38(7-8):1119-39
pubmed: 18668442
Am J Hum Genet. 2019 Jul 3;105(1):89-107
pubmed: 31204013
Am J Hum Genet. 2017 Oct 5;101(4):539-551
pubmed: 28942963
Nat Genet. 2016 May;48(5):481-7
pubmed: 27019110
Nat Commun. 2017 Feb 27;8:14519
pubmed: 28240266
Nat Biotechnol. 2013 Dec;31(12):1102-10
pubmed: 24270849
Nat Genet. 2016 Mar;48(3):245-52
pubmed: 26854917
Nature. 2017 Feb 9;542(7640):186-190
pubmed: 28146470
J Intern Med. 2004 Feb;255(2):188-205
pubmed: 14746556
Science. 2016 Apr 29;352(6285):600-4
pubmed: 27126046
Nat Genet. 2017 Dec;49(12):1758-1766
pubmed: 29083408
Cell Stem Cell. 2017 Apr 6;20(4):558-570.e10
pubmed: 28388432
Nat Commun. 2018 May 8;9(1):1825
pubmed: 29739930
PLoS Genet. 2019 Jul 3;15(7):e1008229
pubmed: 31269066
Cell. 2013 Sep 26;155(1):70-80
pubmed: 24074861
Nat Genet. 2018 Jul;50(7):968-978
pubmed: 29915430
Nature. 2016 Aug 4;536(7614):41-47
pubmed: 27398621
PLoS Genet. 2017 Mar 9;13(3):e1006646
pubmed: 28278150
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16237-42
pubmed: 12444248
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Bioinformatics. 2016 Jan 15;32(2):283-5
pubmed: 26395773
Nat Genet. 2020 Jun;52(6):626-633
pubmed: 32424349
Nat Rev Drug Discov. 2013 Aug;12(8):581-94
pubmed: 23868113
PLoS Genet. 2014 May 15;10(5):e1004383
pubmed: 24830394
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Clin Chem. 2009 Mar;55(3):407-19
pubmed: 19168552
Nature. 2017 Oct 11;550(7675):204-213
pubmed: 29022597
Science. 2012 May 11;336(6082):740-3
pubmed: 22582263
Science. 2017 Dec 8;358(6368):1237-1238
pubmed: 29217551
Nat Genet. 2019 Apr;51(4):592-599
pubmed: 30926968
Science. 2019 Oct 18;366(6463):351-356
pubmed: 31601707
Nat Genet. 2018 Jul;50(7):956-967
pubmed: 29955180
Sci Adv. 2020 Sep 10;6(37):
pubmed: 32917697
Biopreserv Biobank. 2015 Oct;13(5):311-9
pubmed: 26484571
Am J Hum Genet. 2021 Jan 7;108(1):25-35
pubmed: 33308443
Clin Pharmacol Ther. 2008 Sep;84(3):362-9
pubmed: 18500243
Nat Genet. 2019 Mar;51(3):568-576
pubmed: 30804563
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Hum Mol Genet. 2015 Jun 15;24(12):3305-13
pubmed: 25743184
PLoS Genet. 2019 Jan 22;15(1):e1007889
pubmed: 30668570
J R Stat Soc Series B Stat Methodol. 2020 Dec;82(5):1273-1300
pubmed: 37220626
Nature. 2019 Aug;572(7769):323-328
pubmed: 31367044
Genet Epidemiol. 2020 Sep 10;:
pubmed: 32964524
PLoS Genet. 2010 Apr 01;6(4):e1000888
pubmed: 20369019
Nat Genet. 2017 Dec;49(12):1676-1683
pubmed: 29058715
J Lipid Res. 2004 Aug;45(8):1429-36
pubmed: 15175362
Am J Hum Genet. 2016 Dec 1;99(6):1245-1260
pubmed: 27866706
Nucleic Acids Res. 2018 Jan 4;46(D1):D971-D976
pubmed: 29036324