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Gilly, A. ; Park, Y.C.* ; Png, G. ; Barysenka, A. ; Fischer, I. ; Bjørnland, T.* ; Southam, L. ; Suveges, D.* ; Neumeyer, S. ; Rayner, N.W. ; Tsafantakis, E.* ; Karaleftheri, M.* ; Dedoussis, G.* ; Zeggini, E.

Whole-genome sequencing analysis of the cardiometabolic proteome.

Nat. Commun. 11:6336 (2020)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations (P < 7.45 × 10-11) across the allele frequency spectrum, all of which replicate in an independent cohort (n = 1605, 18.4x WGS). We identify for the first time replicating evidence for rare-variant cis-acting protein quantitative trait loci for five genes, involving both coding and noncoding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genetic Architecture; Receptor; Identification; Chemokines; Expression; Framework; Proteins; Samples; Complex; Antigen
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 11, Issue: 1, Pages: , Article Number: 6336 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status
Institute(s) Institute of Translational Genomics (ITG)
Grants Projekt DEAL