High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10⁻⁸) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10⁻¹²⁶) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10⁻⁴⁴) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10⁻³⁴). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

To study the changes in blood volume and hormones controlling sodium and water homeostasis after infusions of 0.9% saline, Gelofusine (4% succinylated gelatin in 0.7% saline, weight-average molecular weight 30 kD), and Voluven (6% hydroxyethyl starch in 0.9% saline, weight-average molecular weight 130 kD) in healthy volunteers. Randomized, three-way crossover study. University teaching hospital. Ten healthy adult male volunteers. Volunteers received 1-L infusions of 0.9% saline, Gelofusine, and Voluven over 1 hr on three occasions. Body weight, hematocrit, serum biochemistry, and plasma concentrations of vasopressin, aldosterone, brain natriuretic peptide, and total renin were measured before infusion and hourly thereafter for 6 hrs. Changes in body water, blood volume, and extravascular fluid volume were calculated. Although changes in body weight (total body water) after the infusions were similar, blood volume expansion by the two colloids was significantly greater than that produced by 0.9% saline (p < .01). At the end of infusions, 68%, 21%, and 16% of the infused volumes of 0.9% saline, Gelofusine, and Voluven, respectively, had escaped from the intravascular space to the extravascular space. Over the 6 hrs, the magnitude and duration of blood volume expansion by the two colloids were similar (p = .70). There were no significant differences in urinary volume, osmolality, and sodium content after the three infusions. Hormonal changes were similar after the three infusions, with the increase in natriuretic peptide being transient. The reduction in aldosterone and total renin concentrations was more sustained. The effects of Gelofusine and Voluven were similar despite the 100 kD difference in weight-average molecular weight. Excretion of an acute fluid load containing sodium and chloride may be dependent on a sustained suppression of the renin-angiotensin-aldosterone system rather than on natriuretic peptides.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.