Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
06 04 2023
06 04 2023
Historique:
received:
28
06
2022
revised:
24
10
2022
accepted:
27
10
2022
medline:
7
4
2023
pubmed:
10
11
2022
entrez:
9
11
2022
Statut:
ppublish
Résumé
Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 248 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analyzing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5× WGS) and Pomak (n = 1537; 18.4× WGS), we detect 301 independently associated pQTL variants for 170 proteins, including 12 rare variants (minor allele frequency < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations but have drifted up in the frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including Mep1b for high-density lipoprotein (HDL) levels, and describe a knock-out (KO) Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships and demonstrate the importance of isolated populations in pQTL analysis.
Identifiants
pubmed: 36349687
pii: 6812863
doi: 10.1093/hmg/ddac275
pmc: PMC10077504
doi:
Substances chimiques
Blood Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1266-1275Subventions
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R026408/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R026408/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : U. MC_UU_00007/10
Pays : United Kingdom
Organisme : Arthritis Research UK
Pays : United Kingdom
Organisme : Chief Scientist Office
ID : CZB/4/710
Pays : United Kingdom
Organisme : European Research Council
ID : ERC-2011-StG 280559- SEPI
Pays : International
Organisme : Wellcome Trust
ID : 098051
Pays : United Kingdom
Organisme : Chief Scientist Office
ID : CZB/4/276
Pays : United Kingdom
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
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