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. 2025 Mar 25;16(1):2913.

doi: 10.1038/s41467-025-58152-3.

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Marie C Sadler^{1

2

3}, Alexander Apostolov³, Caterina Cevallos⁴, Chiara Auwerx^{1

2

3

4}, Diogo M Ribeiro³, Russ B Altman⁵, Zoltán Kutalik^{6

7

8}

Affiliations

¹ University Center for Primary Care and Public Health, Lausanne, Switzerland.
² Swiss Institute of Bioinformatics, Lausanne, Switzerland.
³ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁴ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁵ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁶ University Center for Primary Care and Public Health, Lausanne, Switzerland. zoltan.kutalik@unil.ch.
⁷ Swiss Institute of Bioinformatics, Lausanne, Switzerland. zoltan.kutalik@unil.ch.
⁸ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. zoltan.kutalik@unil.ch.

PMID: 40133288
PMCID: PMC11937416
DOI: 10.1038/s41467-025-58152-3

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Marie C Sadler et al. Nat Commun. 2025.

. 2025 Mar 25;16(1):2913.

doi: 10.1038/s41467-025-58152-3.

Authors

Marie C Sadler^{1

2

3}, Alexander Apostolov³, Caterina Cevallos⁴, Chiara Auwerx^{1

2

3

4}, Diogo M Ribeiro³, Russ B Altman⁵, Zoltán Kutalik^{6

7

8}

Affiliations

¹ University Center for Primary Care and Public Health, Lausanne, Switzerland.
² Swiss Institute of Bioinformatics, Lausanne, Switzerland.
³ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁴ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁵ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁶ University Center for Primary Care and Public Health, Lausanne, Switzerland. zoltan.kutalik@unil.ch.
⁷ Swiss Institute of Bioinformatics, Lausanne, Switzerland. zoltan.kutalik@unil.ch.
⁸ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. zoltan.kutalik@unil.ch.

PMID: 40133288
PMCID: PMC11937416
DOI: 10.1038/s41467-025-58152-3

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.

Conflict of interest statement

Competing interests: MCS has been consulting for 5 Prime Sciences at the time of the submission; however, this study was performed separately with no relationship to 5 Prime Sciences. The results and opinions expressed in this paper do not represent those of 5 Prime Sciences. The other authors declare that they have no competing interests.

Update of

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications.
Sadler MC, Apostolov A, Cevallos C, Ribeiro DM, Altman RB, Kutalik Z. Sadler MC, et al. medRxiv [Preprint]. 2024 Apr 7:2024.04.06.24305415. doi: 10.1101/2024.04.06.24305415. medRxiv. 2024. Update in: Nat Commun. 2025 Mar 25;16(1):2913. doi: 10.1038/s41467-025-58152-3. PMID: 38633781 Free PMC article. Updated. Preprint.

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. 2025 Mar 5:2025:10.17912/micropub.biology.001515.

doi: 10.17912/micropub.biology.001515. eCollection 2025.

Characterization and comparison of Schizosaccharomyces pombe cdc15 temperature-sensitive mutants

Lesley A Turner¹, Aleksandar Vjestica^{2

3}, Alaina H Willet¹, Snezhana Oliferenko^{2

4

5}, Kathleen L Gould¹

Affiliations

¹ Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, US.
² Temasek Life Sciences Laboratory, Singapore 117604, Singapore.
³ Current address: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁴ Current address: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London, SE1 1UL, UK.
⁵ Current address: The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

PMID: 40114852
PMCID: PMC11923602
DOI: 10.17912/micropub.biology.001515

Characterization and comparison of Schizosaccharomyces pombe cdc15 temperature-sensitive mutants

Lesley A Turner et al. MicroPubl Biol. 2025.

. 2025 Mar 5:2025:10.17912/micropub.biology.001515.

doi: 10.17912/micropub.biology.001515. eCollection 2025.

Authors

Lesley A Turner¹, Aleksandar Vjestica^{2

3}, Alaina H Willet¹, Snezhana Oliferenko^{2

4

5}, Kathleen L Gould¹

Affiliations

¹ Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, US.
² Temasek Life Sciences Laboratory, Singapore 117604, Singapore.
³ Current address: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁴ Current address: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King's College London, London, SE1 1UL, UK.
⁵ Current address: The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

PMID: 40114852
PMCID: PMC11923602
DOI: 10.17912/micropub.biology.001515

Abstract

The F-BAR protein Cdc15 is essential for cytokinesis in the fission yeast Schizosaccharomyces pombe , playing a key scaffolding role and connecting the actomyosin-based cytokinetic ring to the plasma membrane. Here, we compared cdc15 temperature-sensitive mutants isolated in multiple genetic screens. We determined the mutations within each cdc15 mutant allele and analyzed their growth at different temperatures. Additionally, we report a new cdc15 allele that highlights the requirement for Cdc15 in the recruitment of the early secretory pathway to the cellular division site. The new mutants described here expand the toolkit for studying cytokinesis in S. pombe .

Conflict of interest statement

The authors declare that there are no conflicts of interest present.

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