Whole genome sequencing analysis of the cardiometabolic proteome

Arthur Gilly, Young-Chan Park, Grace Png, Thea Bjornland, Lorraine Southam, Daniel Suveges, Sonja Neumeyer, Iris Fischer, Andrei Barysenka, N. William Rayner, Emmanouil Tsafantakis, Maria Karaleftheri (+2 others)
2019 biorxiv/medrxiv  
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 conduct high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals to fully assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance. We discover 132 independent sequence variant associations ( <7.45×10 ) across the allele frequency spectrum,
more » ... 44 new -acting and 11 new acting loci, all of which replicate in an independent cohort (n=1,605, 18.4x WGS). We identify replicating evidence for rare-variant -acting protein quantitative trait loci for five genes, involving both coding and non-coding variation. We find causal links between protein biomarkers and cardiovascular, inflammatory and immune-related diseases. We construct and validate polygenic risk scores that explain up to 45% of protein level variation, and find significant correlation between genetically-predicted biomarker levels and cardiovascular disease risk in UK Biobank.
doi:10.1101/854752 fatcat:h6qq65njuzghzicxoehfj23ti4