Fig. 1: Study design.

a Drug response study design using electronic health records (EHRs) from the UK and All of Us biobanks. Baseline (orange) and post-treatment (green) phenotypes were extracted from EHRs or biobank assessment visits before and after the first recorded prescription, respectively. Different timings relative to the first prescription were tested as well as the use of single and average values over multiple baseline and post-treatment measures if available. Drug response phenotypes defined by the 1) absolute and 2) relative logarithmic difference in post-treatment and baseline biomarker measures were tested for ten cardiometabolic medication-phenotype pairs: LDL cholesterol (LDL-C), total cholesterol (TC) and HDL cholesterol (HDL-C) response to statins (blue); HbA1c response to metformin (orange); systolic blood pressure (SBP) response to antihypertensives (green, ACE-inhibitors (ACEi), calcium channel blockers (CCBs) and diuretics); SBP and heart rate (HR) response to beta blockers (purple). b Discovery genetic association analyses were conducted in the UK Biobank and replicated in the All of Us research program on common variants (GWAS analysis) and rare variants through burden tests. c Follow-up analyses compared the genetics of baseline, longitudinal change and drug response genetics including polygenic risk score (PRS) analysis.