| Title: | Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities |
| Journal: | Nature Communications |
| Published: | 3 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40032831/ |
| DOI: | https://doi.org/10.1038/s41467-025-56695-z |
| URL: | https://www.nature.com/articles/s41467-025-56695-z.pdf |
Publication 15660
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Abstract
Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal (https://public.cgr.astrazeneca.com/t2d-pgs/v1/).</p>
14 Keywords
- Aged
- Biomarkers
- Blood Proteins
- Comorbidity
- Diabetes Mellitus, Type 2
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Proteomics
- United Kingdom
21 Authors
- Douglas P. Loesch
- Manik Garg
- Dorota Matelska
- Dimitrios Vitsios
- Xiao Jiang
- Scott C. Ritchie
- Benjamin B. Sun
- Heiko Runz
- Christopher D. Whelan
- Rury R. Holman
- Robert J. Mentz
- Filipe A. Moura
- Stephen D. Wiviott
- Marc S. Sabatine
- Miriam S. Udler
- Ingrid A. Gause-Nilsson
- Slavé Petrovski
- Jan Oscarsson
- Abhishek Nag
- Dirk S. Paul
- Michael Inouye
2 Applications
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
| 65851 | Large-scale proteomic profiling to facilitate genetics-guided drug discovery and precision medicine: The UK Biobank - Pharma Proteomics Project (UKB-PPP) |
Enabling scientific discoveries that improve human health