Abstract
We performed exome-wide association studies to identify genetic variants that influence systolic or diastolic blood pressure or confer susceptibility to hypertension in Japanese. The exome-wide association studies were performed with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays and with 14,678 subjects, including 8215 individuals with hypertension and 6463 controls. The relation of genotypes of 41,843 single nucleotide polymorphisms to systolic or diastolic blood pressure was examined by linear regression analysis. After Bonferroni's correction, 44 and eight polymorphisms were significantly (P < 1.19 × 10−6) associated with systolic or diastolic blood pressure, respectively, with six polymorphisms (rs12229654, rs671, rs11066015, rs2074356, rs3782886, rs11066280) being associated with both systolic and diastolic blood pressure. Examination of the relation of allele frequencies to hypertension with Fisher's exact test revealed that 100 of the 41,843 single nucleotide polymorphisms were significantly (P < 1.19 × 10−6) associated with hypertension. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that five polymorphisms (rs150854849, rs202069030, rs139012426, rs12229654, rs76974938) were significantly (P < 1.25 × 10−4) associated with hypertension. The polymorphism rs12229654 was thus associated with both systolic and diastolic blood pressure and with hypertension. Six polymorphisms (rs12229654 at 12q24.1, rs671 of ALDH2, rs11066015 of ACAD10, rs2074356 and rs11066280 of HECTD4, and rs3782886 of BRAP) were found to be associated with both systolic and diastolic blood pressure, with those at 12q24.1 or in ACAD10 or BRAP being novel determinants of blood pressure in Japanese.
Highlights
Hypertension is a major risk factor for coronary artery disease and stroke [1], with a heritability estimated to be ~30% [2]
We examined the relation of genotypes for 41,843 single nucleotide polymorphisms (SNPs) that passed quality control to systolic or diastolic blood pressure (BP) by linear regression analysis
We have shown that rs12229654 at 12q24.1 was significantly associated with both systolic and diastolic BP as well as with hypertension and that rs671 of aldehyde dehydrogenase 2 family gene (ALDH2), rs11066015 of acylCoA dehydrogenase family member 10 gene (ACAD10), rs2074356 and rs11066280 of HECTD4, and rs3782886 of BRCA1 associated protein gene (BRAP) were significantly associated with both systolic and diastolic BP
Summary
Hypertension is a major risk factor for coronary artery disease and stroke [1], with a heritability estimated to be ~30% [2]. Most of the genetic variants identified in these studies have a minor allele frequency (MAF) of ≥5% and a small individual effect size. Given that these common variants explain only a fraction of the heritability of hypertension, low-frequency (0.5% ≤ MAF < 5%) or rare (MAF < 0.5%) variants with larger effect sizes likely contribute to the genetic architecture of this condition [11]. We have performed exome-wide association studies (EWASs) with the use of exome array–based genotyping methods to identify single nucleotide polymorphisms (SNPs)—in particular, low-frequency or rare coding variants with moderate to large effect sizes— that confer susceptibility to elevated BP or hypertension in Japanese. We applied Illumina human exome arrays that provide coverage of functional SNPs in entire exons including low-frequency and rare variants
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