Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study
Date
2007
DOI
Authors
O'Donnell, Christopher
Cupples, L. Adrienne
D'Agostino, Ralph B.
Hoffmann, Udo
Hwang, Shih-Jen
Ingellson, Erik
Liu, Chunyu
Polak, Joseph
Version
OA Version
Citation
2007. "Genome-wide association study for subclinical atherosclerosis in
major arterial territories in the NHLBI's Framingham Heart Study," BMC Medical Genetics.
vol. 8 issue. Suppl 1 .
Abstract
INTRODUCTION:Subclinical atherosclerosis (SCA) measures in multiple
arterial beds are heritable phenotypes that are associated with increased incidence of
cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA
measurements in the community-based Framingham Heart Study.METHODS:Over 100,000 single
nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345
subjects from 310 families. We calculated sex-specific age-adjusted and
multivariable-adjusted residuals in subjects tested for quantitative SCA phenotypes,
including ankle-brachial index, coronary artery calcification and abdominal aortic
calcification using multi-detector computed tomography, and carotid intimal medial thickness
(IMT) using carotid ultrasonography. We evaluated associations of these phenotypes with
70,987 autosomal SNPs with minor allele frequency [greater than or equal to] 0.10, call rate
[greater than or equal to] 80%, and Hardy-Weinberg p-value [greater than or equal to] 0.001
in samples ranging from 673 to 984 subjects, using linear regression with generalized
estimating equations (GEE) methodology and family-based association testing (FBAT). Variance
components LOD scores were also calculated.RESULTS:There was no association result meeting
criteria for genome-wide significance, but our methods identified 11 SNPs with p <
10-5 by GEE and five SNPs with p < 10-5 by FBAT for multivariable-adjusted
phenotypes. Among the associated variants were SNPs in or near genes that may be considered
candidates for further study, such as rs1376877 (GEE p < 0.000001, located in ABI2)
for maximum internal carotid artery IMT and rs4814615 (FBAT p = 0.000003, located in PCSK2)
for maximum common carotid artery IMT. Modest significant associations were noted with
various SCA phenotypes for variants in previously reported atherosclerosis candidate genes,
including NOS3 and ESR1. Associations were also noted of a region on chromosome 9p21 with
CAC phenotypes that confirm associations with coronary heart disease and CAC in two recently
reported genome-wide association studies. In linkage analyses, several regions of
genome-wide linkage were noted, confirming previously reported linkage of internal carotid
artery IMT on chromosome 12. All GEE, FBAT and linkage results are provided as an
open-access results resource at
http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:The
results from this GWAS generate hypotheses regarding several SNPs that may be associated
with SCA phenotypes in multiple arterial beds. Given the number of tests conducted,
subsequent independent replication in a staged approach is essential to identify genetic
variants that may be implicated in atherosclerosis.