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. 2018 Feb 28;19(3):688. doi: 10.3390/ijms19030688

Table 2.

Results from Next-Generation Sequencing Studies.

N Technology Design Population BP Trait Statistical Analysis Main Results References
1851 WES Haplotype association analysis for ULK4 and MAP4 genes within the GAW19 data set Mexican American SBP, DBP, HTN SKAT; SKAT-O; SKAT-C

  • 36 rare haplotype blocks associated with BP in ULK4 gene and 10 in MAP4 gene

 Datta et al. [61]
1985 unrelated subjects and 1140 relatives WES Screening of SLC12A3, SLC12A1 and KCNJ1 genes exons to identify rare variants within FHS offspring cohort Largely whites of European descent SBP, DBP Two-tailed paired t-test

  • 30 different mutations observed

  • Mean long-term SBP among mutation carriers was 6.3 mmHg lower than the mean of the cohort (p = 0.0009). For DBP, mean effect was −3.4 mmHg (p = 0.003)

 Ji et al. [62]
4178 Target-re-sequencing Case-cohort study design within the CHARGE Targeted Sequencing Study on 6 BP loci European SBP, DBP, PP, MAP Kernel association test

  • None of the common variants reached statistical significance threshold of p = 0.0001

  • Rare variation was not significantly associated with any of the BP measures

 Morrison et al. [63]
92 (HYPERGENES study)2722 (BP cohort)2013 (HTN cohort) Target-re-sequencing Target re-sequencing of a 140-Kb DNA region of Chr. 7 to identify causal or functional variants tagged by the rs3918226 SNP Flemish SBP, DBP, HTN Multivariable-adjusted models

  • 61 novel variants detected by DNA sequencing and confirmed by array-based genotyping

  • rs3918226 remained the SNP most closely associated with HTN

  • The risk allele was associated with lower transcriptional activity of the eNOS gene

 Salvi et al. [64]
103 WGS Case-control study on rare variants in unrelated subjects within GAW18 data set Mexican American SBP, DBP, HTN qMSAT; C-alpha; CMC

  • Rare variants in SETX gene intronic region were significantly associated, as aggregate, with hypertension (OR = 9.5, 95% CI (3.43, 28.70); p = 8.8 × 10−7)

 Wang and Wei. [65]
Discovery: 14,497 in first stage and 3459 in second stage WES To examine the impact of rare variants in CHARGE and ESP studies with meta-analysis of two-stage discovery cohorts European and African ancestry SBP, DBP, PP, MAP T1; SKAT

  • 95 rare coding variants identified in CLCN6 associated, in aggregate, with decreased BP (3–4 mmHg), independent of the tagging SNP rs17367504 previously identified

  • The effect size was about four- to six-fold larger than previous common BP variants from GWAS

 Yu et al. [66]
142 WGS Test for the effects of both rare and common variants across the whole genome of unrelated individuals within the GAW18 study Mexican American SBP, DBP, HTN FBAT; GCTA; SKAT

  • Significant windows within Chr. 3 were reported for associations with SBP and DBP. The most represented gene was MAP4

 Zhao et al. [67]
1509 unrelated subjects; 256 individuals in 47 families WGS and WES To apply CAPL-burden and CAPL-SKAT tests to the GAW19 data set using the combined family and case–control data for HTN (GAW19) Mexican American SBP, DBP, HTN CAPL-burden; CAPL-SKAT

  • None of the tests for the top 10 genes passed the multiple testing correction threshold (p = 3.4 × 10−6)

 Lin et al. [68]
142 WGS WGS and gene expression joint analysis in relation to SBP, DBP, and HTN (GAW19) Mexican American SBP, DBP, HTN Weighted U approach

  • No gene reached statistical significance after adjusting for multiple testing

 Tong et al. [69]
1851 WES To apply W-test on real NGS data set of hypertensive disorder (GAW19) Mexican American SBP, DBP, HTN W-test

  • MACROD1/LRP16 locus was associated with HTN after Bonferroni correction (OR = 3.8; p = 6.1 × 10−7)

 Sun et al. [70]
275 trios WGS To analyse rare variants within ADCY5 and UBE2E2 genes in parent-child trios (GAW18) Mexican American SBP, DBP, HTN Trio-SVM

  • ADCY5 and UBE2E2 genes showed marginal association with HTN with p = 3.2 × 10−4 for ADCY5 and p = 0.035 for UBE2E2

 Lu and Cantor. [71]
103 unrelated individuals WGS To analyse rare variants from Chr. 3 (GAW18) Mexican American SBP, DBP, HTN SKAT-O

  • No significant results in the analysis of real phenotype data (p = 5.6 × 10−5 for coding variants; p = 6.9 × 10−5 for changing variants; p = 1.1 × 10−4 for damaging variants)

 Derkach et al. [72]
783 (GWAS); 506 (WGS) WGS To apply USR algorithm to data from GAW18 Mexican American SBP, DBP, HTN USR algorithm

  • 23 promising genes and 3 significant pathways relevant to HTN identified (p < 5.28 × 10−3)

 Cao et al. [73]

Sample number (N), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Pressure (PP), Mean Artery Pressure (MAP), Hypertension (HTN), Single Nucleotide Polymorphism (SNP), Genome-Wide Association Studies (GWAS), Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), Genetic Analysis Workshop (GAW), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), Exome Sequencing Project (ESP), Sequence Kernel Association Test (SKAT), Optimal Unified Test (SKAT-O), SKAT-Combined (SKAT-C), Quality-based Multivariate Score Association Test (qMSAT), Combined Multivariate and Collapsing (CMC), Family-based Association Test (FBAT), Genome-wide Complex Trait Analysis (GCTA), Combined Association in the Presence of Linkage (CAPL), support vector machine (SVM), Unified Sparse Regression (USR), Odds Ratio (OR).