PT  - JOURNAL ARTICLE
AU  - Arthur Gilly
AU  - Young-Chan Park
AU  - Grace Png
AU  - Andrei Barysenka
AU  - Iris Fischer
AU  - Thea Bjornland
AU  - Lorraine Southam
AU  - Daniel Suveges
AU  - Sonja Neumeyer
AU  - N. William Rayner
AU  - Emmanouil Tsafantakis
AU  - Maria Karaleftheri
AU  - George Dedoussis
AU  - Eleftheria Zeggini
TI  - Whole genome sequencing analysis of the cardiometabolic proteome
AID  - 10.1101/854752
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 854752
4099  - http://biorxiv.org/content/early/2020/04/07/854752.short
4100  - http://biorxiv.org/content/early/2020/04/07/854752.full
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 (22.5x) whole-genome sequencing (WGS) in 1,328 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=1,605, 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 non-coding 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.