Despite significant pharmacogenomic (PGx) insights into key biological pathways influencing drug response, the polygenic contribution to dose variability and the potential of electronic health records (EHRs) for maintenance dose estimation remain largely unexplored. To address this gap, we leveraged longitudinal drug purchase data from the Estonian Biobank to derive medication dose metrics and investigate genetic associations using polygenic scores (PGS) and genome-wide association studies (GWAS). Daily doses per purchase as well as median and maximum doses as consolidated metrics across purchases were derived for statins, warfarin, metoprolol, antidepressants, and antipsychotics. Sample sizes ranged from 684 (antipsychotics) to 20,642 (statins), with median doses reflecting typical maintenance doses. The PGS for the indicator trait was significant for the daily dose of statins (coronary heart disease PGS; beta=0.02, P=5.9x10-10) and metoprolol (systolic blood pressure PGS, beta=0.03, P=7.5x10-13). The PGS for body mass index was linked to daily doses of statins (beta=0.02, P=6.4x10-7), metoprolol (beta=0.03, P=1.4x10-14), and warfarin (beta=0.03, P=0.001), whereas the PGS for educational attainment showed opposing associations with statins (beta=-0.01, P=5.9x10-4) and antidepressants (beta=0.01, P=0.002). Median and maximum doses had similar but weaker associations. GWAS confirmed signals for metoprolol (CYP2D6, P=1.1x10-20) and warfarin (CYP2C9, P=8.9x10-60; VKORC1, P=4.2x10-148), as well as enrichment of PGx signals for individual statins (P=0.02 for simvastatin, P=0.03 for atorvastatin). Altogether, these findings illustrate the feasibility and value of deriving medication doses from EHRs and highlight the role of polygenic liability and PGx factors in dose variability.

The authors have declared no competing interest.

This research was supported by EU Horizon 2020 Research and Innovation Programme under Grant agreement No. 964874 (Realment), by the Estonian Research Council grant PSG1028, grant PRG2625, grant PRG1197, and grant PRG1911, by the Estonian Ministry of Education and Research grant TK214, and Estonian Center of Genomics/Roadmap II grant TT17, by the Swedish Research Council grant No. 2021-02732, and by the University of Tartu grant PLTGI24925.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the Estonian Committee on Bioethics and Human Research at the Estonian Ministry of Social Affairs (24 March 2020, nr 1.1-12/624).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

GWAS summary statistics are publicly available as provided in respective publications. Individual-level data at EstBB can only be accessed through EstBB. Further info about access is provided at https://genomics.ut.ee/en/content/estonian-biobank.