A genome-wide association study identifies a novel candidate locus at the DLGAP1 gene with susceptibility to resistant hypertension in the Japanese population

Yasuo Takahashi,Satoshi Asai,Michiaki Kubo,Koichi Matsuda,Keiko Yamazaki,Yoichiro Kamatani

doi:10.1038/s41598-021-98144-z

Yasuo Takahashi, Satoshi Asai + Show 4 more

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https://doi.org/10.1038/s41598-021-98144-z

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Abstract

Numerous genetic variants associated with hypertension and blood pressure are known, but there is a paucity of evidence from genetic studies of resistant hypertension, especially in Asian populations. To identify novel genetic loci associated with resistant hypertension in the Japanese population, we conducted a genome-wide association study with 2705 resistant hypertension cases and 21,296 mild hypertension controls, all from BioBank Japan. We identified one novel susceptibility candidate locus, rs1442386 on chromosome 18p11.3 (DLGAP1), achieving genome-wide significance (odds ratio (95% CI) = 0.85 (0.81–0.90), P = 3.75 × 10−8) and 18 loci showing suggestive association, including rs62525059 of 8q24.3 (CYP11B2) and rs3774427 of 3p21.1 (CACNA1D). We further detected biological processes associated with resistant hypertension, including chemical synaptic transmission, regulation of transmembrane transport, neuron development and neurological system processes, highlighting the importance of the nervous system. This study provides insights into the etiology of resistant hypertension in the Japanese population.

Highlights

Numerous genetic variants associated with hypertension and blood pressure are known, but there is a paucity of evidence from genetic studies of resistant hypertension, especially in Asian populations
To clarify the genetic architecture of resistant hypertension, we conducted a genome-wide association studies (GWASs) in a Japanese population consisting of 2705 resistant hypertension cases and 21,296 mild hypertension controls (Supplementary Fig. S1)
We evaluated the possibility of population substructure for our sample population by comparison to HapMap samples using principal component analysis (PCA)

Summary

Introduction

Numerous genetic variants associated with hypertension and blood pressure are known, but there is a paucity of evidence from genetic studies of resistant hypertension, especially in Asian populations. Elevation of circulating aldosterone level has been identified in the majority of patients with resistant h ypertension[12,13,14], drawing attention to the importance of aldosterone in the Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. A few studies with a comprehensive genetic approach, genome-wide association studies (GWASs), have identified some significant loci for susceptibility to resistant hypertension in the US population[30,31,32,33]. We performed a GWAS to identify novel genetic loci associated with resistant hypertension in the Japanese population

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