Inter-individual variation in blood pressure (BP) arises in part from sequence variants within numerous enhancers modulating expression of an unknown number of causal genes. We propose that these genes are active in tissues relevant to BP physiology and can be identified from tissue epigenomic data and genotypes of BP-phenotyped individuals. We used the ENCODE project's H3K27ac and ATAC-seq data from the heart, adrenal gland, kidney, and artery to comprehensively identify all cis regulatory elements (CREs) in these tissues to estimate the impact of all common human single nucleotide variants (SNVs) in CREs on gene expression, using machine learning methods. To identify specific genes, we integrated these results through a gene-wise association test against BP. We conducted analyses in two separate large-scale cohorts: 77,822 individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) of Kaiser Permanente North California and 315,270 individuals from the UK Biobank (UKB). We identified 309, 259, 331 and 367 genes (FDR<0.05) for diastolic BP (DBP), and 191, 184, 204, and 204 genes for systolic BP (SBP), in the artery, kidney, heart, and adrenal gland, respectively, in GERA; 50-70% of these genes were replicated in the UKB and is significantly higher than the 12-15% expected by chance (P <10-4). These results enabled the prediction of tissue expression of these 988-2,875 putative BP-genes in individual participants of both cohorts to construct an expression polygenic score (exPGS). This score explained ~27% of the reported SNV heritability (h2, 21%), substantially higher than that expected from prior studies. Additionally, we utilized these methods to provide dual-modality supporting evidence, CRE and expression-based, for the causality of genes previously detected by GWAS.

Prabhu Mathiyalagan is a cofounder and CEO of Benthos Prime Central (Houston, TX, USA).

This study was supported by National Institutes of Health grants HL086694, HL141980, and HL128782 to A.C.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Following an NYU Langone Health Institutional Review Board (IRB) self-certification form, this study was deemed non-human subject research and, therefore, did not require a full review by the NYU Langone Health Institutional Review Board. One human renal cortex sample was obtained de-identified from the National Disease Research Interchange (NDRI; protocol: RCHA201001A; PI: A. Chakravarti). Two additional renal cortex samples were obtained from the University of Michigan and Gift of Life Michigan. This study was conducted with the informed consent of all participants and was approved by the University of Michigan Institutional Review Board (IRB number: HUM00107869; PI: S.K. Ganesh).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes