Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

Published on Sep 7, 2020in Nature Genetics38.33
路 DOI :10.1038/S41588-020-0682-6
Jie Zheng21
Estimated H-index: 21
(UoB: University of Bristol),
Valeriia Haberland8
Estimated H-index: 8
(UoB: University of Bristol)
+ 31 AuthorsTom R. Gaunt70
Estimated H-index: 70
(UoB: University of Bristol)
Sources
Abstract
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (https://www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets. Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.
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The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046). ERG is supported by the National Institutes of Health (NIH) Awards R35HG010718, R01HG011138, R01GM140287, and NIH/NIA AG068026. MAW, MA, and GK are supported by grants from the National Institute on Aging (NIA): null U01 AG061359, RF1 AG057452, and RF1 AG059093). JCZ is supported by a 4-year Wellcome...
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