WHOLE GENOME SURVIVAL ANALYSIS OF 144,286 PEOPLE FROM UK BIOBANK IDENTIFIES NOVEL LOCI ASSOCIATED WITH BLOOD PRESSURE

Abstract

Objective: Hypertension is a leading heritable cardiovascular risk factor worldwide associated with over 1000 common single nucleotide polymorphisms (SNPs). However, these SNPs only explain about half of its heritability, suggesting the presence of yet-to-be-identified genetic factors influencing this trait. This study used longitudinal UK Biobank data to discover novel genetic loci related to hypertension, addressing limitations in cross-sectional GWAS approaches. Design and method: The study sourced disease outcomes from diverse records (in-patient, self-reported, primary care, death registry, and time-to-event data) within the UK Biobank. It spanned from October 2010 (the last participant's enrolment) to the latest ’Essential hypertension’ diagnosis on October 2022, encompassing 12 years of follow-up. Utilizing whole genome sequence (WGS) data, our analysis employed the R package ‘SPACox’ for a genome-wide survival analysis, integrating Age, Age2, Sex, BMI, and 10 principal components as covariates. The WGS data underwent rigorous quality control (QC) measures, excluding SNPs with low call rates(<0.90), Hardy–Weinberg equilibrium test P-values<1×10-15, or minor allele frequencies less than 0.01. Results: The analysis included 21,248 hypertension cases and 123,038 controls, totalling 144,286 participants, with 58.0% women (average age - 55.3±0.0279 years). Post-genotype QC, 6,319,822 million SNPs underwent analysis, revealing 31 variants (P-value<5×10–08), including 29 new SNPs—15 in Fibrillin-2 (FBN2) and 2 in Junctophilin-2 (JPH2) genes. Subsequent Mendelian randomization studies, employing two identified SNPs (rs17677724 and rs1014754), revealed a genetically induced decrease in heart FBN2 expression and an increase in adrenal gland JPH2 expression was causally linked to increased blood pressure (P-Value =1.66×10-06, 3.19×10-06). Thereafter, FinnGen dataset PheWAS analysis reaffirmed rs17677724's (Beta = 0.492, P = 7.4×10-09) and rs1014754's (Beta = 0.0225, P = 4.8×10-05) positive association to hypertension, among 2,727 traits assessed in 377,277 individuals. Lastly, rs1014754 associated positively with kallistatin (Beta = 0.031, P = 0.0225) while rs17677724 negatively associated with Renin (Beta = -0.036, P = 0.0435), in the Fenland study (10,708 participants, 10.2 million variants, 4775 protein targets), suggesting a counter-regulatory response to high blood pressure. Conclusions: Our genome-wide time-to-event analysis unveils new genetic loci associated with hypertension, illuminating their role in hypertension via FBN2 and JPH2 expression.