Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping

Proteogenomics studies generate hypotheses on protein function and provide genetic evidence for drug target prioritization. Most previous work has been conducted using affinity-based proteomics approaches. These technologies face challenges, such as uncertainty regarding target identity, non-specifi...

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Published inNature communications Vol. 15; no. 1; p. 989
Main Authors Suhre, Karsten, Venkataraman, Guhan Ram, Guturu, Harendra, Halama, Anna, Stephan, Nisha, Thareja, Gaurav, Sarwath, Hina, Motamedchaboki, Khatereh, Donovan, Margaret K R, Siddiqui, Asim, Batzoglou, Serafim, Schmidt, Frank
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 02.02.2024
Nature Portfolio
Subjects
Affinity
Binders
Binding
Blood
Gene mapping
Humans
Mass spectrometry
Mass Spectrometry - methods
Mass spectroscopy
Mutant Proteins
Nanoparticles
Peptide mapping
Peptides
Peptides - analysis
Proteins
Proteins - analysis
Proteogenomics - methods
Proteomics
Proteomics - methods
Scientific imaging
Therapeutic targets
Workflow
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Summary:Proteogenomics studies generate hypotheses on protein function and provide genetic evidence for drug target prioritization. Most previous work has been conducted using affinity-based proteomics approaches. These technologies face challenges, such as uncertainty regarding target identity, non-specific binding, and handling of variants that affect epitope affinity binding. Mass spectrometry-based proteomics can overcome some of these challenges. Here we report a pQTL study using the Proteograph™ Product Suite workflow (Seer, Inc.) where we quantify over 18,000 unique peptides from nearly 3000 proteins in more than 320 blood samples from a multi-ethnic cohort in a bottom-up, peptide-centric, mass spectrometry-based proteomics approach. We identify 184 protein-altering variants in 137 genes that are significantly associated with their corresponding variant peptides, confirming target specificity of co-associated affinity binders, identifying putatively causal cis-encoded proteins and providing experimental evidence for their presence in blood, including proteins that may be inaccessible to affinity-based proteomics.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-45233-y