405 Uncovering population-specific signals and hundreds of new loci from a multi-ancestry study of blood pressure traits in over 2.5M individuals

Objectives/Goals: To identify population-specific and ancestry-informed genetic loci for blood pressure traits, characterize X chromosome associations, and evaluate evidence for evolutionary pressures influencing blood pressure risk across ancestries, which may be used downstream clinically for personalized medicine and drug target identification. Methods/Study Population: We conducted multi-ancestry and ancestry-stratified genome-wide association studies (GWAS) of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) across >2.5M individuals (40% non-European) from 16 cohorts and biobanks. Analyses were adjusted for age, age², sex, body mass index, and the first 10 principal components. Fixed-effects meta-analyses were followed by SuSiEx cross-population fine-mapping to identify ancestry-specific loci. We evaluated genetic differentiation using the fixation index (FST) and allele frequency directionality using the sign test to infer potential evolutionary pressures. Results/Anticipated Results: Multi-ancestry meta-analyses identified 2,406 significant independent loci for SBP (1,594 novel), 2,358 DBP (1,509 novel), and 2,312 PP (1,432 novel). Chromosome X analyses revealed 8 SBP, 80 DBP, and 8 PP loci. SuSiEx fine-mapping identified ancestry-specific signals, including a pulse pressure SNP near CTSL (Asian-specific) and a DBP SNP in CACNA1D (African-specific). Sign tests indicated enrichment of DBP risk alleles when comparing African and Asian populations and when comparing Admixed American and Asian populations (p < 0.01), supported by elevated FST values for variants with larger effect sizes. These findings suggest that ancestry-specific selection may influence blood pressure regulation. Discussion/Significance of Impact: This is the largest and most ancestrally diverse blood pressure genetics study to date and one of few to include X chromosome analyses, which enabled discovery of thousands of novel and population-specific loci and revealed evolutionary and biological insights that may advance precision medicine for hypertension.