title: The role of rare variants in systolic blood pressure: analysis of ExomeChip data in HyperGEN African Americans.
abstract: 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.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Sung
authors.forename: Jacob
authors.initials: J
authors.lastname: Basson
authors.forename: Nuo
authors.initials: N
authors.lastname: Cheng
authors.forename: Khanh-Dung H
authors.initials: KD
authors.lastname: Nguyen
authors.forename: Priyanka
authors.initials: P
authors.lastname: Nandakumar
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.forename: Victor G
authors.initials: VG
authors.lastname: Dávila-Román
authors.forename: Dabeeru C
authors.initials: DC
authors.lastname: Rao
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D001741:Black or African American / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics*; D059472:Exome; D014644:Genetic Variation; D006801:Humans; D013599:Systole