| Title: | Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications |
| Journal: | Nature Communications |
| Published: | 25 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40133288/ |
| DOI: | https://doi.org/10.1038/s41467-025-58152-3 |
Publication 15851
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Abstract
Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 932-28,880). Our discovery analyses in participants of European ancestry recover previously reported pharmacogenetic signals at genome-wide significance level (APOE, LPA and SLCO1B1) and a novel rare variant association in GIMAP5 with HbA1c response to metformin. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. We also found polygenic risk scores to predict drug response, though they explained less than 2% of the variance. In summary, we present an EHR-based framework to study the genetics of drug response and systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in 41,732 UK Biobank and 14,277 All of Us participants.</p>
16 Keywords
- Aged
- Antihypertensive Agents
- Biological Specimen Banks
- Cardiovascular Diseases
- Electronic Health Records
- Female
- Genome-Wide Association Study
- Glycated Hemoglobin
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Liver-Specific Organic Anion Transporter 1
- Male
- Metformin
- Middle Aged
- Pharmacogenetics
- United Kingdom
7 Authors
- Marie C. Sadler
- Alexander Apostolov
- Caterina Cevallos
- Chiara Auwerx
- Diogo M. Ribeiro
- Russ B. Altman
- Zoltán Kutalik
1 Application
| Application ID | Title |
|---|---|
| 16389 | Exploring Diet/Lifestyle factors as causes and modifiers of genetic determinants of obesity and metabolic traits |
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