Framingham Heart Study Allelic Spectrum Project

This substudy phs000307 Framingham Allelic Spectrum Project includes the generation of deep coverage targeted re-sequencing and variant identification for 216 genes in the Framingham Heart Study (FHS) sample collection, produced as part of NHLBI's Medical Resequencing projects. Summary level phenotypes for the Framingham Cohort study participants can be viewed at the top-level study page [phs000007](./study.cgi?study_id=phs000007) Framingham Cohort. Individual level phenotype data and molecular data for all Framingham top-level study and substudies are available by requesting Authorized Access to the Framingham Cohort study [phs000007](./study.cgi?study_id=phs000007).

Cardiovascular disease (CVD) is the leading cause of death in the US, affecting 64 million Americans and costing over 368 billion dollars annually. To elucidate causes of CVD, NIH established the Framingham Heart Study (FHS) in 1948. In 1971, 5000 adult children and spouses of original FHS participants expanded the initial population-based cohort. The FHS Offspring cohort has now been followed for a decade beyond their 6th cardiovascular examination, providing incidence and prevalence data for CVD. These data indicate that diabetes mellitus, hyperlipidemia, hypertension, left ventricular hypertrophy, cigarette smoking, obesity, sedentary life style, and family history are major risk factors for development of atherosclerosis, coronary artery disease, myocardial infarction, heart failure, and stroke.

The role of genetic variation is documented by substantial heritability to cardiovascular disease risk factors, left ventricular hypertrophy and subclinical atherosclerosis, as well as evidence for familial aggregation of common forms of cardiovascular disease such as coronary heart disease, heart failure and sudden cardiac death. Molecular genetic studies of Mendelian disorders (and, to a much more limited degree, association studies of common variants) have led to the identification of human gene mutations that influence important CVD phenotypes. Hundreds of mutations in over 100 genes are known to produce major effects on serum cholesterol, lipoprotein and glucose levels, blood pressure via renal handling of salt and water, myocardial contractile function and ventricular morphology, and cardiac electrophysiologic properties. The phenotypes produced by single gene defects (hypercholesterolemia, diabetes, hypertension, cardiac hypertrophy, and cardiac arrhythmias) are remarkably similar to the common cardiovascular disease risk factors found broadly within the general population, raising the hypothesis that the full allelic spectrum of CVD genes may, in sum, contribute substantially to overall CVD prevalence.

To provide a comprehensive assessment of the frequency and distribution of rare and common allelic variation in previously defined cardiovascular genes in general populations with defined incident cardiovascular risks and disease, we have assembled a collaborative group that includes investigators with considerable expertise in the study of CVD genes and leading investigators in the FHS.