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Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies

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Zhang, Jingning, Dutta, Diptavo, Köttgen, Anna, Tin, Adrienne, Schlosser, Pascal, Grams, Morgan E., Harvey, Benjamin, CKDGen Consortium +4 more·2022·Nature Genetics
DOI 10.1038/s41588-022-01051-wPMC PMC9236177

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Abstract

Abstract Improved understanding of the proteome 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 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 in EA and 1,605 in AA, which had significant cis- single-nucleotide polymorphism (SNP) associations. Estimates of cis-heritability (cis-h2) for plasma proteins were similar across EA and AA (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 (median R2/cis-h2 = 0.79 for EA and 0.69 for AA). 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).

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  • We and Zhang et al. detected CSs for 58 (59.2%) protein cis regions using data from cohorts of European ancestry.

    “We and Zhang et al.71 detected CSs for 58 (59.2%) protein cis regions using data from cohorts of European ancestry”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [71]

    The Results (Fine Mapping; page unavailable) report that Zhang et al. generated 95% credible sets using European-ancestry data, supporting their part of the comparison. Our copy does not establish that the citing study and Zhang et al. both detected credible sets for the same 58 (59.2%) protein cis regions; that overlap requires the citing study’s data. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Our CSs for cis associations contained an average of 15.76 variants, whereas Zhang et al. used imputed genotyping data and reported an average of 21.29 variants.

    “Our CSs for cis associations contained an average of 15.76 variants, whereas Zhang et al. used imputed genotyping data and reported an average of 21.29 variants71.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [71]

    The Methods section (‘Plasma protein data and genetic data’; page unavailable) says the ARIC genotypes were imputed to the TOPMed reference panel. The Results (‘Fine Mapping’; page unavailable) report an average of 21.29 variants per 95% credible set for the European-ancestry group, but 12.11 for the African-ancestry group. The cited sentence omits that 21.29 applies specifically to the European-ancestry group, not to the study overall. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Only a limited number of pQTL studies have conducted fine mapping as a post-GWAS analysis.

    “Only a limited number of pQTL studies have conducted fine mapping9,71 as one of the post-GWAS analyses.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [71]

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Authors
Zhang, J., Dutta, D., Köttgen, A., Tin, A., Schlosser, P., Grams, M. E., Harvey, B., CKDGen Consortium, Yu, B., Boerwinkle, E., Coresh, J., & Chatterjee, N.
Affiliations
  • Johns Hopkins University (US)
  • The University of Texas Health Science Center at Houston (US)
  • Baylor College of Medicine (US)
Corresponding author
Chatterjee, Nilanjan
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-05
Volume
54
Issue
5
Pages
593-602
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01051-w
PMC
PMC9236177
OpenAlex
W4225284570
Cited by
373
References
11
Citations by year
2026: 84 · 2025: 110 · 2024: 116 · 2023: 46 · 2022: 15 · 2021: 2
FWCI
44.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (1 R01 HG010480-01)
  • Deutsche Forschungsgemeinschaft (Project-ID 431984000 – SFB 1453)
  • U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR073178)
  • EQUIP Program for Medical Scientists, Faculty of Medicine, University of Freiburg
  • U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK124399)
  • Bloomberg Distinguished Professorship Endowment fund available to N.C.
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL148218, R01 HL134320)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
plasma proteome, proteome-wide association study, African American ancestry, serum uric acid, gout, interleukin-1 receptor antagonist, anakinra, Atherosclerosis Risk in Communities Study
MeSH terms
Gout, Humans, Genetic Predisposition to Disease, Proteome, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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