Integrating Mouse and Human Genetic Data to Move beyond GWAS and Identify Causal Genes in Cholesterol Metabolism.
GWAS
SREBP2
Sestrin1
cholesterol
co-expression networks
computational biology
human genetics
lipoproteins
mouse genetics
plasma lipids
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
07 04 2020
07 04 2020
Historique:
received:
25
02
2019
revised:
14
01
2020
accepted:
20
02
2020
pubmed:
21
3
2020
medline:
4
9
2021
entrez:
21
3
2020
Statut:
ppublish
Résumé
Identifying the causal gene(s) that connects genetic variation to a phenotype is a challenging problem in genome-wide association studies (GWASs). Here, we develop a systematic approach that integrates mouse liver co-expression networks with human lipid GWAS data to identify regulators of cholesterol and lipid metabolism. Through our approach, we identified 48 genes showing replication in mice and associated with plasma lipid traits in humans and six genes on the X chromosome. Among these 54 genes, 25 have no previously identified role in lipid metabolism. Based on functional studies and integration with additional human lipid GWAS datasets, we pinpoint Sestrin1 as a causal gene associated with plasma cholesterol levels in humans. Our validation studies demonstrate that Sestrin1 influences plasma cholesterol in multiple mouse models and regulates cholesterol biosynthesis. Our results highlight the power of combining mouse and human datasets for prioritization of human lipid GWAS loci and discovery of lipid genes.
Identifiants
pubmed: 32197071
pii: S1550-4131(20)30074-7
doi: 10.1016/j.cmet.2020.02.015
pmc: PMC7184639
mid: NIHMS1580422
pii:
doi:
Substances chimiques
Heat-Shock Proteins
0
SESN1 protein, human
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
741-754.e5Subventions
Organisme : NIA NIH HHS
ID : R56 AG056771
Pays : United States
Organisme : BLRD VA
ID : I01 BX004031
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG050135
Pays : United States
Organisme : NIA NIH HHS
ID : R00 AG041765
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056771
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG051974
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062328
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147097
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL123021
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007665
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL123021
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138907
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests D.W.L. has received funding from, and is a scientific advisory board member of, Aeonian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.
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