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Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Macdonald-Dunlop, Erin ; Klaric, Lucija ; Folkersen, Lasse ; Timmers, Paul R H J ; Gustafsson, Stefan ; Hua Zhao, Jing ; Eriksson, Niclas ; Richmond, Anne ; Enroth, Stefan and Mattsson-Carlgren, Niklas LU orcid , et al. (2021)
Abstract
We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using... (More)
We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology. (Less)
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organization
publishing date
type
Working paper/Preprint
publication status
published
subject
pages
27 pages
publisher
medRxiv
DOI
10.1101/2021.08.03.21261494
language
English
LU publication?
yes
id
9e0ee81d-7c6f-4ee7-be38-a8fab21a874c
date added to LUP
2021-10-04 11:43:02
date last changed
2023-12-16 03:00:20
@misc{9e0ee81d-7c6f-4ee7-be38-a8fab21a874c,
  abstract     = {{We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.}},
  author       = {{Macdonald-Dunlop, Erin and Klaric, Lucija and Folkersen, Lasse and Timmers, Paul R H J and Gustafsson, Stefan and Hua Zhao, Jing and Eriksson, Niclas and Richmond, Anne and Enroth, Stefan and Mattsson-Carlgren, Niklas and Zhernakova, Daria V and Magnusson, Martin and Smith, J. Gustav and Hansson, Oskar}},
  language     = {{eng}},
  month        = {{08}},
  note         = {{Preprint}},
  publisher    = {{medRxiv}},
  title        = {{Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases}},
  url          = {{http://dx.doi.org/10.1101/2021.08.03.21261494}},
  doi          = {{10.1101/2021.08.03.21261494}},
  year         = {{2021}},
}