The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports

Abstract

Background: The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies.

Methods: Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests.

Results: The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 +/- 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency > or + 10%, genotype call rate > or = 80%, Hardy-Weinberg equilibrium p-value > or = 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.

Conclusion: We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.

Figure 1

Distribution of Minor Allele Frequency for SNPs in Framingham Sample displayed on dbGaP Website. The percentage of SNPs (X axis) with MAF of zero and in ranges (0,2], (2,4], ..., (48,50] percent (Y axis) in the Framingham sample of 1345 subjects is detailed. For example, approximately 2.5–3% of SNPs in the Affymetrix 100K GeneChip had MAF of zero in the Framingham sample and about 4% had MAF greater than 16 percent and less than or equal to 18 percent. This distribution represents SNPs described on the dbGaP website. The manuscripts only include SNPs with MAF of 10% or more.

Figure 2

Distribution of Affymetrix 100K GeneChip SNPs by distance from known genes. The X axis is the distance from known genes and the Y axis is the number of SNPs according to each distance. Blue represents monomorphic SNPs, maroon is for SNPs with MAF < 10% and green is for SNPs with MAF ≥ 10%.

Figure 3

Observed versus Expected p-values (-log base 10 scale) for Mean Fasting Glucose in Offspring Exams 1 to 7 (Left) and for Mean Fasting High Density Lipoprotein in Offspring Exams 1 to 7 (Right). Blue dots are for GEE and red dots for FBAT.