Extended Data Fig. 6: Drug-target Mendelian randomization analysis overview of anti-diabetics, lipid-modulating targets, and antihypertensives.

Diagram depicts flow diagram and details of the drug-target MR analyses of the cardiometabolic targets on mvAge (N = 1,958,774). Prior to step 1, colocalization analysis was employed to prioritize protein-coding targets for the screen. See Methods and Supplementary Methods for details on selection and identification of the individual targets in the three broad drug classes (anti-diabetics, lipid-modulating targets, and antihypertensive). In step 2, cis-instrumentation was performed using genome-wide association study (GWAS) of biomarkers that are the primary indications of pharmacological modulation of these targets. For antidiabetics, GWAS data of HbA1c (N = 344,182) was used; for lipid-modulating targets, several lipid subfractions including LDL-C (N = 440,546), triglycerides (N = 441,016), and HDL-C (N = 403,943) were used; and for antihypertensives, GWAS data of SBP (N = 436,419). Independent variants (LD R² < 0.2) at P-values < 5 × 10⁻⁸) were extracted, and cis-instruments constructed for each target, which exposure variants were then extracted from the mvAge GWAS (outcome), harmonized, and then analyzed using multiple MR methods (steps 3 and 4). See Methods and Supplementary Methods for further details. MR, Mendelian randomization; LD, linkage disequilibrium. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; SBP, systolic blood pressure.