Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk.
colocalizataion
genome-wide association study
metabolomics
transcriptome-wide association study
transcriptomics
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
06 10 2022
06 10 2022
Historique:
received:
22
04
2022
accepted:
09
08
2022
pubmed:
3
9
2022
medline:
12
10
2022
entrez:
2
9
2022
Statut:
ppublish
Résumé
Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.
Identifiants
pubmed: 36055244
pii: S0002-9297(22)00359-7
doi: 10.1016/j.ajhg.2022.08.007
pmc: PMC9606383
pii:
doi:
Substances chimiques
Glycerophospholipids
0
SLC22A5 protein, human
0
Solute Carrier Family 22 Member 5
0
Bilirubin
RFM9X3LJ49
Carnitine
S7UI8SM58A
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1727-1741Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK093757
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES033634
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062370
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008853
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK105561
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062370
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119380
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL151328
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131961
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK072193
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM138121
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 HG000024
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.E.L. is an employee and stockholder of Regeneron Pharmaceuticals. N.O.S. has received research funding from Regeneron Pharmaceuticals unrelated to this work. E.B.F. is an employee and stockholder of Pfizer.
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