Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Abstract

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. Combined with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure raising genetic variants on future cardiovascular disease risk.

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

“…Our eQTL analysis identified 60 novel loci with eQTLs in arterial and 20 in adrenal tissue (Supplementary Table 9), substantially increasing those identified in our previously published GWAS on ~140K UKB individuals10. An example is SNP rs31120122 which defines an aortic eQTL affecting expression of the MED8 gene within the SZT2 locus.…”

Genome-Wide Association Studies of Hypertension and Several Other Cardiovascular Diseases

“…Furthermore, the GRS generated by combination of 107 loci by Warren et al [11] showed that the group with GRS in the lowest quintile had an SBP approximately 9–10 mm Hg lower than those with GRS in the highest quintile. Reductions in BP of such a magnitude might lead to significantly lower cardiovascular morbidity and mortality among hypertensive patients.…”

“…The latest GWAS by Warren et al [11] identified multiple loci involved in BP regulation, including angiotensin-converting enzyme, voltage-dependent calcium channel auxiliary subunit, metallo­endopeptidase/neutral endopeptidase, adrenergic β 2B receptor, and phosphodiesterase 5a. Moreover, in the pathway analysis, they also showed an enrichment of pathways associated with cardiovascular disease, including the α-adrenergic pathway, CXCR4 chemokine signaling pathway, endothelin system, and angiotensin-receptor pathways.…”

“…With dense 1000 Genomes Project and UK10K imputation, they yielded a data set with ∼9.8 million variants for the meta-analysis. With the help of major international consortia for parallel replication, they included GWAS data from 330,956 individuals in total and reported 107 significant loci, among which 24 were associated with systolic BP (SBP), 41 with diastolic BP (DBP), and 42 with PP [11]. …”

CONTRIBUTION OF GENETIC MARKERS AND PRODUCTION FACTORS IN THE DEVELOPMENT OF ARTERIAL HYPERTENSION IN MEN IN AN ORGANIzED WORKERS COHORT OF MACHINE-BUILDING PLANT

“…Генетическая основа АГ включает в себя множество полиморфных локусов. Так, с помощью полногеномных исследований ассо-циаций (genome-wide association studies -GWAS) было выявлено более 100 генов различных сигналь-ных путей и еще больше однонуклеотидных поли-морфизмов (ОНП), ассоциированных с повышен-ным артериальным давлением и гипертонией [8][9][10]. Однако, несмотря на выявление на сегодняшний день большого количества генов и ОНП, ассоциированных с АГ, каждый в отдельности генетический вариант имеет слабое влияние на развитие АГ, объясняет очень малую долю наследственности в развитии заболевания и, таким образом, имеет ограниченную предсказатель-ную ценность [11].…”