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Whole genome sequencing analysis of the cardiometabolic proteome

View ORCID ProfileArthur Gilly, View ORCID ProfileYoung-Chan Park, View ORCID ProfileGrace Png, View ORCID ProfileAndrei Barysenka, View ORCID ProfileIris Fischer, View ORCID ProfileThea Bjornland, View ORCID ProfileLorraine Southam, View ORCID ProfileDaniel Suveges, View ORCID ProfileSonja Neumeyer, View ORCID ProfileN. William Rayner, Emmanouil Tsafantakis, Maria Karaleftheri, View ORCID ProfileGeorge Dedoussis, View ORCID ProfileEleftheria Zeggini
doi: https://doi.org/10.1101/854752
Arthur Gilly
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
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Young-Chan Park
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
3University of Cambridge, Cambridge, UK
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Grace Png
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
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Andrei Barysenka
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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Iris Fischer
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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Thea Bjornland
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
4Department of Mathematical Sciences, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
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Lorraine Southam
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
5Wellcome Centre for Human Genetics, Oxford, UK
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Daniel Suveges
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
6European Bioinformatics Institute, Wellcome Genome Campus, Hinxton CB10 1SH, UK
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Sonja Neumeyer
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
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N. William Rayner
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
7Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
8Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Emmanouil Tsafantakis
9Anogia Medical Centre, Anogia, Greece
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Maria Karaleftheri
10Echinos Medical Centre, Echinos, Greece
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George Dedoussis
11Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Greece
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Eleftheria Zeggini
1Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
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  • For correspondence: eleftheria.zeggini@helmholtz-muenchen.de
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Abstract

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.

Footnotes

  • Corrected author order. Updated results.

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Posted April 07, 2020.
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Whole genome sequencing analysis of the cardiometabolic proteome
Arthur Gilly, Young-Chan Park, Grace Png, Andrei Barysenka, Iris Fischer, Thea Bjornland, Lorraine Southam, Daniel Suveges, Sonja Neumeyer, N. William Rayner, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Eleftheria Zeggini
bioRxiv 854752; doi: https://doi.org/10.1101/854752
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Whole genome sequencing analysis of the cardiometabolic proteome
Arthur Gilly, Young-Chan Park, Grace Png, Andrei Barysenka, Iris Fischer, Thea Bjornland, Lorraine Southam, Daniel Suveges, Sonja Neumeyer, N. William Rayner, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Eleftheria Zeggini
bioRxiv 854752; doi: https://doi.org/10.1101/854752

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