Adrenergic Alpha-1 Pathway Is Associated with Hypertension among Nigerians in a Pathway-focused Analysis

<div><h3>Background</h3><p>The pathway-focused association approach offers a hypothesis driven alternative to the agnostic genome-wide association study. Here we apply the pathway-focused approach to an association study of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in 1614 Nigerians with genome-wide data.</p> <h3>Methods and Results</h3><p>Testing of 28 pathways with biological relevance to hypertension, selected <em>a priori</em>, containing a total of 101 unique genes and 4,349 unique single-nucleotide polymorphisms (SNPs) showed an association for the adrenergic alpha 1 (ADRA1) receptor pathway with hypertension (p<0.0009) and diastolic blood pressure (p<0.0007). Within the ADRA1 pathway, the genes <em>PNMT</em> (hypertension P_gene<0.004, DBP P_gene<0.004, and SBP P_gene<0.009, and <em>ADRA1B</em> (hypertension P_gene<0.005, DBP P_gene<0.02, and SBP P_gene<0.02) displayed the strongest associations. Neither <em>ADRA1B</em> nor <em>PNMT</em> could be the sole mediator of the observed pathway association as the ADRA1 pathway remained significant after removing <em>ADRA1B</em>, and other pathways involving <em>PNMT</em> did not reach pathway significance.</p> <h3>Conclusions</h3><p>We conclude that multiple variants in several genes in the ADRA1 pathway led to associations with hypertension and DBP. SNPs in ADRA1B and PNMT have not previously been linked to hypertension in a genome-wide association study, but both genes have shown associations with hypertension through linkage or model organism studies. The identification of moderately significant (10⁻²>p>10⁻⁵) SNPs offers a novel method for detecting the “missing heritability” of hypertension. These findings warrant further studies in similar and other populations to assess the generalizability of our results, and illustrate the potential of the pathway-focused approach to investigate genetic variation in hypertension.</p>