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

Karsten Suhre (), Guhan Ram Venkataraman, Harendra Guturu, Anna Halama, Nisha Stephan, Gaurav Thareja, Hina Sarwath, Khatereh Motamedchaboki, Margaret K. R. Donovan, Asim Siddiqui, Serafim Batzoglou and Frank Schmidt
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Karsten Suhre: Weill Cornell Medicine-Qatar, Education City
Guhan Ram Venkataraman: Seer, Inc., Redwood City
Harendra Guturu: Seer, Inc., Redwood City
Anna Halama: Weill Cornell Medicine-Qatar, Education City
Nisha Stephan: Weill Cornell Medicine-Qatar, Education City
Gaurav Thareja: Weill Cornell Medicine-Qatar, Education City
Hina Sarwath: Weill Cornell Medicine-Qatar, Education City
Khatereh Motamedchaboki: Seer, Inc., Redwood City
Margaret K. R. Donovan: Seer, Inc., Redwood City
Asim Siddiqui: Seer, Inc., Redwood City
Serafim Batzoglou: Seer, Inc., Redwood City
Frank Schmidt: Weill Cornell Medicine-Qatar, Education City

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45233-y

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