TY - JOUR
T1 - The role of rare variants in systolic blood pressure
T2 - Analysis of exomechip data in HyperGEN African Americans
AU - Sung, Yun Ju
AU - Basson, Jacob
AU - Cheng, Nuo
AU - Nguyen, Khanh Dung H.
AU - Nandakumar, Priyanka
AU - Hunt, Steven C.
AU - Arnett, Donna K.
AU - Dávila-Román, Victor G.
AU - Rao, Dabeeru C.
AU - Chakravarti, Aravinda
N1 - Publisher Copyright:
© 2015 S. Karger AG, Basel.
PY - 2015/4/6
Y1 - 2015/4/6
N2 - Cardiovascular diseases are among the most significant health problems in the United States today, with their major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although GWAS have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans, these variants collectively explain <2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here, we report the results from rare-variant analysis of systolic BP using 94,595 rare and low-frequency variants (minor allele frequency, MAF, <5%) from the Illumina exome array genotyped in 2,045 HyperGEN AAs. In addition to single-variant analysis, 4 gene-level association tests were used for analysis: burden and family-based SKAT tests using MAF cutoffs of 1 and 5%. The gene-based methods often provided lower p values than the single-variant approach. Some consistency was observed across these 4 gene-based analysis options. While neither the gene-based analyses nor the single-variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, 6 of the 16 most promising genes are biologically plausible with physiological connections to BP regulation.
AB - Cardiovascular diseases are among the most significant health problems in the United States today, with their major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although GWAS have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans, these variants collectively explain <2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here, we report the results from rare-variant analysis of systolic BP using 94,595 rare and low-frequency variants (minor allele frequency, MAF, <5%) from the Illumina exome array genotyped in 2,045 HyperGEN AAs. In addition to single-variant analysis, 4 gene-level association tests were used for analysis: burden and family-based SKAT tests using MAF cutoffs of 1 and 5%. The gene-based methods often provided lower p values than the single-variant approach. Some consistency was observed across these 4 gene-based analysis options. While neither the gene-based analyses nor the single-variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, 6 of the 16 most promising genes are biologically plausible with physiological connections to BP regulation.
KW - Burden tests
KW - ExomeChip
KW - Family studies
KW - Gene-based analysis
KW - Rare variants
KW - SKAT
KW - Systolic blood pressure
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U2 - 10.1159/000375373
DO - 10.1159/000375373
M3 - Article
C2 - 25765051
AN - SCOPUS:84924739396
SN - 0001-5652
VL - 79
SP - 20
EP - 27
JO - Human Heredity
JF - Human Heredity
IS - 1
ER -