AUTHOR=Maj Carlo , Salvi Erika , Citterio Lorena , Borisov Oleg , Simonini Marco , Glorioso Valeria , Barlassina Cristina , Glorioso Nicola , Thijs Lutgarde , Kuznetsova Tatiana , Cappuccio Francesco P. , Zhang Zhen-Yu , Staessen Jan A. , Cusi Daniele , Lanzani Chiara , Manunta Paolo TITLE=Dissecting the Polygenic Basis of Primary Hypertension: Identification of Key Pathway-Specific Components JOURNAL=Frontiers in Cardiovascular Medicine VOLUME=9 YEAR=2022 URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.814502 DOI=10.3389/fcvm.2022.814502 ISSN=2297-055X ABSTRACT=Introduction and Objectives

Genome-wide association studies have identified a high number of genetic loci associated with hypertension suggesting the presence of an underlying polygenic architecture. In this study, we aimed to dissect the polygenic component of primary hypertension searching also for pathway-specific components.

Methods

The polygenic risk score (PRS) models, based on the UK biobank genetic signals for hypertension status, were obtained on a target Italian case/control cohort including 561 cases and 731 hyper-normal controls from HYPERGENES, and were then applied to an independent validation cohort composed by multi-countries European-based samples including 1,284 cases and 960 hyper-normal controls.

Results

The resulting genome-wide PRS was capable of stratifying the individuals for hypertension risk by comparing between individuals in the last PRS decile and the median decile: we observed an odds ratio (OR) of 3.62, CI = [2.01, 6.32] (P = 9.01E-07) and 3.22, 95% CI = [2.06, 5.10] (P = 6.47E-08) in the target and validation cohorts, respectively. The relatively high case/control ORs across PRS quantiles corroborates the presence of strong polygenic components which could be driven by an enrichment of risk alleles within the cases but also by potential enrichment of protective alleles in the old normotensive controls. Moreover, novel pathway-specific PRS revealed an enrichment of the polygenic signal attributable to specific biological pathways. Among those the most significantly associated with hypertension status was the calcium signaling pathway together with other mainly related such as the phosphatidylinositol/inositol phosphate pathways.

Conclusions

The development of pathway-specific PRS could prioritize biological mechanisms, according to their contribution to the genetic susceptibility, whose regulations might be a potential pharmacological preventive target.