Complex genetic effects linked to plasma protein abundance in the UK Biobank
Understanding genetic associations of proteins is important for studying the molecular effect of genetic variation. A key component of this is to understand the role of complex genetic effects such as dominance and epistasis that are associated with plasma proteins. Therefore, we develop EIR-auto-GP, a deep learning-based approach, to identify complex effects that are associated with protein quantitative trait loci (pQTLs). Applying this method to the UK Biobank proteomics cohort of 48,594 individuals, we identify 123 proteins that are correlated with non-linear covariates and 15 with genetic dominance and epistasis. We uncover a novel interaction between the ABO and FUT3 loci and demonstrate dominance effects of the ABO locus on plasma levels of pathogen recognition receptors CD209 and CLEC4M. Furthermore, we replicate these findings and the methodology across Olink and mass spectrometry-based cohorts. Our approach presents a systematic, large-scale attempt to identify complex effects of plasma protein levels.
Authors
- Benjamin M. Neale (ORCID: https://orcid.org/0000-0003-1513-6077)
- Ruth J. F. Loos (ORCID: https://orcid.org/0000-0002-8532-5087)
- Jens‐Christian Holm (ORCID: https://orcid.org/0000-0003-4653-342X)
- Henry Webel (ORCID: https://orcid.org/0000-0001-8833-7617)
- Jonas Meisner (ORCID: https://orcid.org/0000-0002-9540-6673)
- Arnór I. Sigurdsson (ORCID: https://orcid.org/0000-0002-3880-9505)
- Roelof A. J. Smit (ORCID: https://orcid.org/0000-0001-9822-6726)
- Zhiyu Yang (ORCID: https://orcid.org/0000-0002-8074-838X)
- Kirstine Ravn (ORCID: https://orcid.org/0000-0002-5079-8095)
- Justus F. Gräf (ORCID: https://orcid.org/0000-0002-8945-5903)
- Simon Rasmussen (ORCID: https://orcid.org/0000-0001-6323-9041)
- Andrea Ganna (ORCID: https://orcid.org/0000-0002-8147-240X)
- Bjarni Jóhann Vilhjálmsson (ORCID: https://orcid.org/0000-0003-2277-9249)
- Roman Thielemann (ORCID: https://orcid.org/0000-0003-2582-6178)
- Matthias Mann (ORCID: https://orcid.org/0000-0003-1292-4799)
- Torben Hansen (ORCID: https://orcid.org/0000-0001-8748-3831)
- Lili Niu (ORCID: https://orcid.org/0000-0003-4571-4368)
Institutions
- Broad Institute (US)
- University of Copenhagen (DK)
- University of Helsinki (FI)
- Aarhus University (DK)
- Novo Nordisk Foundation (DK)
- Copenhagen University Hospital (DK)
- Foundation Center (US)
- Massachusetts General Hospital (US)
- Novo Nordisk (United States) (US)
- Institute for Molecular Medicine Finland (FI)
- European Association for the Study of Obesity (GB)
- Max Planck Institute of Biochemistry (DE)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1038/s41467-025-67235-0
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bristol-Myers Squibb
- Pfizer
- GlaxoSmithKline
- Novartis
- Sanofi
- Biogen
- Celgene
- Hjerteforeningen
- Maze Therapeutics
- Novo Nordisk
- Novo Nordisk Fonden
- Business Finland
- Genentech
- Janssen Biotech