Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Figure 1. Study design and work flow diagram of single variant discovery analyses.

EUR=European, SAS=South Asian, HIS=Hispanic, AA=African American, HTN=hypertension, BP=blood pressure, SBP=systolic blood pressure, DBP= diastolic blood pressure, PP=pulse pressure, N=sample size, MAF=minor allele frequency, P=P-value significance threshold, SNV=single-nucleotide variant, GWS=genome-wide significance *Further details of the selection criteria are provided in the methods.

Figure 2. Overlap of the 30 novel loci associations across SBP, DBP, PP and HTN.

The Venn diagram shows which of the 30 newly identified BP loci are associated with multiple BP traits. Only SNV-BP trait associations that were genome-wide significant (P < 5x10^-8) in the combined discovery and replication meta-analyses are listed for any given BP trait, within the corresponding ancestry dataset that the given locus was validated for (see Tables 1 and 2). The association of RRAS variant with SBP was replicated in the independent samples, but did not achieve GWS in the combined discovery and replication meta-analysis and is therefore only included for SBP. HTN=hypertension, SBP=systolic blood pressure, DBP= diastolic blood pressure, PP=pulse pressure.

Figure 3. Study design for conditional analyses and rare variant gene-based discovery analyses.

RMW=RareMetalWorker, EUR=European, SAS = South Asian, HTN=hypertension, BP=blood pressure, SBP=systolic blood pressure, DBP= diastolic blood pressure, PP=pulse pressure. N=sample size, MAF=minor allele frequency, P=P-value significance threshold, P_cond=conditional P-value significance threshold

Figure 4. Locus plot for A2ML1 and secondary amino acid structure of the gene product.

(a) Locus plot for A2ML1 associated with HTN identified through gene based tests. The variants’ positions along the gene (x axis, based on human genome build 37) and the –log₁₀(P-value of association) (y axis) are indicated. The variants are colour coded: nonsense (black), missense, predicted damaging (blue), and missense (orange). The schematic above the x-axis represents the intron / exon (black vertical bars) structure, the untranslated regions are shown as grey vertical bars. (b) The white box denotes the full-length amino acid sequence for each of the two gene products. Black numbers denote amino acid residue positions of note. Coloured boxes depict putative functional domains (see below). Coloured vertical lines indicate the amino acid substitutions corresponding to the variants depicted in the locus plots above using the same colour coding. Bold, italic indicates the SNV association with smallest P-value. Dark grey – signal peptide sequence. Brown – regions of intramolecular disulfide bonds. For simplicity only those regions coinciding with variants described were indicated. Black – bait region described to interact with proteases. Purple – thiol ester sequence region aiding in interaction with proteases. Light grey – alpha helical regions thought to mediate A2ML1 interaction with LRP1, facilitating receptor-mediated endocytosis.