A genome-wide association study of mass spectrometry proteomics using a nanoparticle enrichment platform
Most studies to date of protein quantitative trait loci (pQTLs) have relied on affinity proteomics platforms, which provide only limited information about the targeted protein isoforms and may be affected by genetic variation in their epitope binding. Here we show that mass spectrometry (MS)-based proteomics can complement these studies and provide insights into the role of specific protein isoform and epitope-altering variants. Using the Seer Proteograph nanoparticle enrichment MS platform, we identified and replicated new pQTLs in a genome-wide association study of proteins in blood plasma samples from two cohorts and evaluated previously reported pQTLs from affinity proteomics platforms. We found that >30% of the evaluated pQTLs were confirmed by MS proteomics to be consistent with the hypothesis that genetic variants induce changes in protein abundance, whereas another 30% could not be replicated and are possibly due to epitope effects, although alternative explanations for nonreplication need to be considered on a case-by-case basis.
Authors
- Jessica Ann Lasky-Su (ORCID: https://orcid.org/0000-0001-6236-4705)
- Hina Sarwath
- Anna Halama (ORCID: https://orcid.org/0000-0003-4910-6255)
- Kevin Mendez (ORCID: https://orcid.org/0000-0002-8832-2607)
- Karsten Suhre (ORCID: https://orcid.org/0000-0001-9638-3912)
- Ryan Smith (ORCID: https://orcid.org/0000-0001-7362-8753)
- Frank Schmidt (ORCID: https://orcid.org/0000-0001-5406-3988)
- Gaurav Thareja (ORCID: https://orcid.org/0000-0003-2277-6400)
- Nisha Stephan (ORCID: https://orcid.org/0000-0002-8133-2597)
- Harendra Guturu (ORCID: https://orcid.org/0000-0003-1501-4694)
- Varun B. Dwaraka (ORCID: https://orcid.org/0000-0001-9033-3092)
- Qingwen Chen (ORCID: https://orcid.org/0000-0002-2946-4947)
- Amber Dahlin (ORCID: https://orcid.org/0000-0002-2534-5975)
- Serafim Batzoglou (ORCID: https://orcid.org/0009-0009-1513-8452)
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Cornell University (US)
- Lander Institute (IL)
- Cytodiagnostics (Canada) (CA)
- Weill Cornell Medical College in Qatar (QA)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41588-025-02413-w
- Citations
- 5
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 9.09
Funders
- Qatar Foundation
- Fonds National de la Recherche Luxembourg
- National Institutes of Health
- Qatar National Research Fund