Identification of genetic variants influencing the human plasma proteome
Open accessAbstract
Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis -acting SNPs. We identified and replicated individual cis -acting SNPs (combined P value ranging from 3.1 × 10 −52 to 2.9 × 10 −12 ) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the ɛ4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.
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Genomic sequence variation can lead to differing peptide sequences in the population.
“Genomic sequence variation can lead to differing peptide sequences in the population.(25–27)”
From Putting humpty dumpty back together again: what does protein quantification mean in bottom-up proteomics? (2022) · cites this paper as [25]
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The functional impact of rare variation across the regulatory cascade
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Prospective applications of ultrahigh resolution proteomics in clinical mass spectrometry
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A genome-wide association study of mass spectrometry proteomics using the Seer Proteograph platformPreprint
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Plasma protein levels of young healthy pigs as indicators of disease resilience
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Self-citationImpact of allele‐specific peptides in proteome quantification
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Genetic variants entail type 2 diabetes as an innate immune disorder
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Recent Advancements and Applications of Size Exclusion Chromatography in Modern Analysis
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Pulmonary hypertension: Proteins in the blood
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Peripheral Biomarkers for Depression by Plasma and Serum Proteomics
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Population Proteomics: A Tool to Gain Insights Into the Inflamed Periodontium
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Molecular interaction networks in the analyses of sequence variation and proteomics data
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Detecting Protein Variants within Mass Spectrometry Datasets
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Making Research Code Useful Paradata
Bilderbeek, R. J. C. (2024) · Knowledge management and organizational learning · doi:10.1007/978-3-031-53946-6_3
Zhong, W., Gummesson, A., Tebani, A., Karlsson, M., Hong, M., Schwenk, J. M., Edfors, F., Bergström, G., Fagerberg, L., & Uhlén, M. (2020) · Figshare · doi:10.6084/m9.figshare.12586481
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Ren, Y., Shi, Z., Chen, D., & Hao, P. (2026) · Analytical Chemistry · doi:10.1021/acs.analchem.6c00082
- Authors
- Johansson, Å., Enroth, S., Palmblad, M., Deelder, A. M., Bergquist, J., & Gyllensten, U.
- Affiliations
- Uppsala University (SE)
- Leiden University Medical Center (NL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-03-04
- Volume
- 110
- Issue
- 12
- Pages
- 4673-4678
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3606982
- OpenAlex
- W2082354164
- Cited by
- 82
- References
- 37
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 3 · 2018: 11 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 10 · 2013: 3
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- plasma proteome, genetic variants, heritability, peptide abundance, protein abundance, apolipoprotein E, APOE ε4, regulatory SNPs, non-synonymous mutations, biomarkers, high-throughput mass spectrometry, proteomics
- MeSH terms
- Adolescent, Adult, Alleles, Blood Proteins, Female, Genetic Markers, Humans, Male, Middle Aged, Cohort Studies, Biomarkers, Proteome, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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