Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study. / Peloso, Gina M; Lange, Leslie A; Varga, Tibor V; Nickerson, Deborah A; Smith, Joshua D; Griswold, Michael E; Musani, Solomon; Polfus, Linda M; Mei, Hao; Gabriel, Stacey; Quarells, Rakale Collins; Altshuler, David; Boerwinkle, Eric; Daly, Mark J; Neale, Benjamin; Correa, Adolfo; Reiner, Alex P; Wilson, James G; Kathiresan, Sekar.
In: Circulation. Cardiovascular genetics, Vol. 9, No. 4, 08.2016, p. 368-374.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study
AU - Peloso, Gina M
AU - Lange, Leslie A
AU - Varga, Tibor V
AU - Nickerson, Deborah A
AU - Smith, Joshua D
AU - Griswold, Michael E
AU - Musani, Solomon
AU - Polfus, Linda M
AU - Mei, Hao
AU - Gabriel, Stacey
AU - Quarells, Rakale Collins
AU - Altshuler, David
AU - Boerwinkle, Eric
AU - Daly, Mark J
AU - Neale, Benjamin
AU - Correa, Adolfo
AU - Reiner, Alex P
AU - Wilson, James G
AU - Kathiresan, Sekar
N1 - © 2016 American Heart Association, Inc.
PY - 2016/8
Y1 - 2016/8
N2 - BACKGROUND: The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes.METHODS AND RESULTS: We performed whole-exome sequencing in 3223 black individuals from the Jackson Heart Study and found a total of 729 666 variant sites with minor allele frequency <5%, including 17 263 null variants and 49 929 missense variants predicted to be damaging by in silico algorithms. We tested null and damaging missense variants within each gene for association with 36 cardiovascular traits. We found 3 associations that met our prespecified level of significance (α=1.1×10(-7)). Null and damaging missense variants in PCSK9 were associated with 36 mg/dL lower low-density lipoprotein cholesterol (P=3×10(-21)). Three individuals in their 50s with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) were identified, with one having a coronary artery calcification score in the 83rd percentile despite a low-density lipoprotein cholesterol of 32 mg/dL. A damaging missense variant in HBQ1 (p.G52A) was associated with a 2 pg/cell lower mean corpuscular hemoglobin (P=9×10(-13)) and rare damaging missense variants in VPS13A with higher red blood cell distribution width (P=9.9×10(-8)).CONCLUSIONS: A limited number of null/damaging alleles with a large effect on cardiovascular traits were detectable in ≈3000 black individuals.
AB - BACKGROUND: The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes.METHODS AND RESULTS: We performed whole-exome sequencing in 3223 black individuals from the Jackson Heart Study and found a total of 729 666 variant sites with minor allele frequency <5%, including 17 263 null variants and 49 929 missense variants predicted to be damaging by in silico algorithms. We tested null and damaging missense variants within each gene for association with 36 cardiovascular traits. We found 3 associations that met our prespecified level of significance (α=1.1×10(-7)). Null and damaging missense variants in PCSK9 were associated with 36 mg/dL lower low-density lipoprotein cholesterol (P=3×10(-21)). Three individuals in their 50s with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) were identified, with one having a coronary artery calcification score in the 83rd percentile despite a low-density lipoprotein cholesterol of 32 mg/dL. A damaging missense variant in HBQ1 (p.G52A) was associated with a 2 pg/cell lower mean corpuscular hemoglobin (P=9×10(-13)) and rare damaging missense variants in VPS13A with higher red blood cell distribution width (P=9.9×10(-8)).CONCLUSIONS: A limited number of null/damaging alleles with a large effect on cardiovascular traits were detectable in ≈3000 black individuals.
KW - Adipokines/blood
KW - Adult
KW - African Americans/genetics
KW - Aged
KW - Aged, 80 and over
KW - Algorithms
KW - Biomarkers/blood
KW - Cardiovascular Diseases/blood
KW - Computational Biology
KW - Computer Simulation
KW - Databases, Genetic
KW - Exome
KW - Female
KW - Gene Frequency
KW - Genetic Association Studies
KW - Genetic Markers
KW - Genetic Predisposition to Disease
KW - Humans
KW - Inflammation Mediators/blood
KW - Lipids/blood
KW - Longitudinal Studies
KW - Male
KW - Middle Aged
KW - Mississippi/epidemiology
KW - Mutation, Missense
KW - Phenotype
KW - Proprotein Convertase 9/genetics
KW - Quantitative Trait, Heritable
KW - Risk Factors
U2 - 10.1161/CIRCGENETICS.116.001410
DO - 10.1161/CIRCGENETICS.116.001410
M3 - Journal article
C2 - 27422940
VL - 9
SP - 368
EP - 374
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
SN - 1942-325X
IS - 4
ER -
ID: 242837741