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Large Bi-Ethnic Study of Plasma Proteome Leads to Comprehensive Mapping of cis-pQTL and Models for Proteome-wide Association Studies

View ORCID ProfileJingning Zhang, Diptavo Dutta, Anna Köttgen, View ORCID ProfileAdrienne Tin, Pascal Schlosser, Morgan E. Grams, Benjamin Harvey, Bing Yu, Eric Boerwinkle, Josef Coresh, View ORCID ProfileNilanjan Chatterjee
doi: https://doi.org/10.1101/2021.03.15.435533
Jingning Zhang
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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  • ORCID record for Jingning Zhang
Diptavo Dutta
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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Anna Köttgen
2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
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Adrienne Tin
2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
4MIND Center and Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, USA
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Pascal Schlosser
3Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
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Morgan E. Grams
2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
5Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, US
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Benjamin Harvey
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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Bing Yu
6Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
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Eric Boerwinkle
6Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
7Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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Josef Coresh
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
5Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, US
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Nilanjan Chatterjee
1Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
8Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • ORCID record for Nilanjan Chatterjee
  • For correspondence: nilanjan@jhu.edu
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Abstract

Improved understanding of the genetic architecture of the proteome through studies of larger sample size, ethnic diversity, and advanced methods can facilitate the identification of causal mechanisms for complex traits. We conducted a comprehensive analysis of the common variant cis-regulatory genetic architecture of 4,665 plasma proteins or protein complexes ascertained using an aptamer-based technology from 7,213 European Americans (EA) and 1,871 African Americans (AA) from the Atherosclerosis Risk in Communities (ARIC) cohort study. We identified and fine-mapped 1,992 plasma proteins or protein complexes in EA and 1,605 in AA, with majority overlapping in EA, which had at least one significant single-nucleotide polymorphism (SNP) in cis region. Estimates of cis-heritability (cis-h2) for plasma proteins were similar across the two ethnic groups (median cis-h2 = 0.09 for EA and 0.10 for AA). Elastic-net based models for cis-SNP-based protein prediction produced high accuracy for the EA population (median R2/cis-h2=0.79), and notably for the AA (median R2/cis-h2 = 0.69), despite the much smaller sample size in the latter population. We illustrate the application of these models to conduct proteome-wide association studies (PWAS) for two related complex traits, serum urate and gout, and further conduct conditional analyses to interpret findings in the context of those from transcriptome-wide association studies (TWAS).

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • http://nilanjanchatterjeelab.org/pwas/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Large Bi-Ethnic Study of Plasma Proteome Leads to Comprehensive Mapping of cis-pQTL and Models for Proteome-wide Association Studies
Jingning Zhang, Diptavo Dutta, Anna Köttgen, Adrienne Tin, Pascal Schlosser, Morgan E. Grams, Benjamin Harvey, Bing Yu, Eric Boerwinkle, Josef Coresh, Nilanjan Chatterjee
bioRxiv 2021.03.15.435533; doi: https://doi.org/10.1101/2021.03.15.435533
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Large Bi-Ethnic Study of Plasma Proteome Leads to Comprehensive Mapping of cis-pQTL and Models for Proteome-wide Association Studies
Jingning Zhang, Diptavo Dutta, Anna Köttgen, Adrienne Tin, Pascal Schlosser, Morgan E. Grams, Benjamin Harvey, Bing Yu, Eric Boerwinkle, Josef Coresh, Nilanjan Chatterjee
bioRxiv 2021.03.15.435533; doi: https://doi.org/10.1101/2021.03.15.435533

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