Genome-wide association with select biomarker traits in the Framingham Heart Study

Emelia J. Benjamin, Josée Dupuis, Martin G. Larson, Kathryn L. Lunetta, Sarah L. Booth, Diddahally R. Govindaraju, Sekar Kathiresan, John F. Keaney, Michelle J. Keyes, Jing Ping Lin, James B. Meigs, Sander J. Robins, Jian Rong, Renate Schnabel, Joseph A. Vita, Thomas J. Wang, Peter W.F. Wilson, Philip A. Wolf, Ramachandran S. Vasan

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

Background: Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. Methods: We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507-1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001. Results: With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at http://www.ncbi.nlm.nih.gov/projects/gap/ cgi-bin/study.cgi?id=phs000007. Conclusion: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.

Original languageEnglish (US)
Article numberS11
JournalBMC Medical Genetics
Volume8
Issue numberSUPPL. 1
DOIs
StatePublished - Sep 19 2007
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Genome-wide association with select biomarker traits in the Framingham Heart Study'. Together they form a unique fingerprint.

Cite this