Longitudinal exome-wide association study to identify genetic susceptibility loci for hypertension in a Japanese population

Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) ‘CAAAA’ comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype ‘TGGGT’. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5 , was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time. Hypertension: Uncovering genetic risk in a Japanese population A long-term genetic study reveals gene variants associated with hypertension in a Japanese population. Previous genetic analyses have revealed many hypertension-associated genes in individuals of European ancestry but few of these genes are relevant to hypertension in non-European populations. To address this discrepancy, Yoshiki Yasukochi at Mie University and Japanese colleagues examined the protein-coding portions of the genomes of 6,022 individuals from Inabe City along with their health data from annual check-ups obtained over 11 years. They identified six genetic variants in a region of chromosome 12 and a novel variant on chromosome 3 associated with susceptibility to hypertension. They also identified an East Asian-specific combination of these genes that may protect against the adverse effect of smoking on hypertension. Understanding the role of these gene variants in hypertension will aid the delivery of personal