Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies

Abstract

Background: Hypertension imposes substantial health and economic burden worldwide. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, causing cardiovascular events at higher risk compared with essential hypertension. However, the germline genetic contribution to the susceptibility of PA has not been well elucidated.

Method: We conducted a genome-wide association analysis of PA in the Japanese population and a cross-ancestry meta-analysis combined with UK Biobank and FinnGen cohorts (816 PA cases and 425 239 controls) to identify genetic variants that contribute to PA susceptibility. We also performed a comparative analysis for the risk of 42 previously established blood pressure-associated variants between PA and hypertension with the adjustment of blood pressure.

Results: In the Japanese genome-wide association study, we identified 10 loci that presented suggestive evidence for the association with the PA risk (P<1.0×10^-6). In the meta-analysis, we identified 5 genome-wide significant loci (1p13, 7p15, 11p15, 12q24, and 13q12; P<5.0×10^-8), including 3 of the suggested loci in the Japanese genome-wide association study. The strongest association was observed at rs3790604 (1p13), an intronic variant of WNT2B (odds ratio, 1.50 [95% CI, 1.33-1.69]; P=5.2×10^-11). We further identified 1 nearly genome-wide significant locus (8q24, CYP11B2), which presented a significant association in the gene-based test (P=7.2×10^-7). Of interest, all of these loci were known to be associated with blood pressure in previous studies, presumably because of the prevalence of PA among individuals with hypertension. This assumption was supported by the observation that they had a significantly higher risk effect on PA than on hypertension. We also revealed that 66.7% of the previously established blood pressure-associated variants had a higher risk effect for PA than for hypertension.

Conclusions: This study demonstrates the genome-wide evidence for a genetic predisposition to PA susceptibility in the cross-ancestry cohorts and its significant contribution to the genetic background of hypertension. The strongest association with the WNT2B variants reinforces the implication of the Wnt/β-catenin pathway in the PA pathogenesis.

Keywords: Wnt/β-catenin pathway; genome-wide association analysis; hypertension; primary aldosteronism.

Figure 1.

Manhattan plot for the genome-wide association analysis of primary aldosteronism. Manhattan plots showing −log₁₀(P value) of the genome-wide association study of primary aldosteronism (PA) in the Japanese cohort (A) and meta-analysis (B). The red horizontal line indicates the genome-wide significance threshold (P=5.0×10⁻⁸). We also display a suggestive significance threshold (P=1.0×10⁻⁶) as the blue horizontal line in the Japanese genome-wide association study.

Figure 2.

Forest plots showing the odds ratios of lead variants for genome-wide and nearly genome-wide association loci for PA risk in each cohort. Forest plots for the odds ratios (ORs) of rs3790604 (A), rs2023843 (B), rs145725189 (C), rs4980379 (D), rs35486 (E), and rs35442752 (F) on the risk of primary aldosteronism (PA). Each forest plot shows the estimated ORs and 95% CIs from the cohort-specific genome-wide association study results. The variant name, chromosome position, and risk alleles and nonrisk alleles are shown above each plot. The size of the square representing the OR is proportional to the effective sample size of each cohort. RAF indicates risk allele frequency; and UKB, UK Biobank.

Figure 3.

Comparison of the genetic risk of blood pressure-associated variants for primary aldosteronism and hypertension. A, The plot represents the OR of BP-associated variants for hypertension (horizontal axis) and PA (vertical axis) in the Japanese cohort. B, The plot represents −log₁₀(P value) of the case-case association analysis between PA and hypertension with the adjustment for BP in the Japanese cohort. The vertical axis shows −log₁₀(P value), with the higher risk effects on PA and hypertension shown at the above and below the horizontal axis, respectively. The dots representing individual variants are displayed in the descending order from higher positive association with PA to higher positive association with hypertension. In both panels, the color of dots corresponds to the legend: risk-associated loci for PA identified in this GWAS meta-analysis (red), genes in which somatic mutations are reported to be associated with aldosterone-producing adenoma or aldosterone- and cortisol-cosecreting adrenal tumors (orange), and others (blue). The effect alleles are based on alleles that are reported to increase BP. BP indicates blood pressure; GWAS, genome-wide association study; HTN, hypertension; OR, odds ratio; and PA, primary aldosteronism.