TY - JOUR
T1 - Whole-genome sequencing analysis of the cardiometabolic proteome
AU - Gilly, Arthur
AU - Park, Young Chan
AU - Png, Grace
AU - Barysenka, Andrei
AU - Fischer, Iris
AU - Bjørnland, Thea
AU - Southam, Lorraine
AU - Suveges, Daniel
AU - Neumeyer, Sonja
AU - Rayner, N. William
AU - Tsafantakis, Emmanouil
AU - Karaleftheri, Maria
AU - Dedoussis, George
AU - Zeggini, Eleftheria
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85097381511&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-20079-2
DO - 10.1038/s41467-020-20079-2
M3 - Article
C2 - 33303764
AN - SCOPUS:85097381511
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6336
ER -
