JHS Allelic Spectrum Project

This sub-study [phs000498](./study.cgi?study_id=phs000498) JHS Allelic Spectrum Seq contains genotype derived from sequence data and selected phenotype of subjects available from the [phs000498](./study.cgi?study_id=phs000498) study. Summary level phenotypes for the NHLBI JHS Cohort study participants can be viewed at the top-level study page [phs000286](http://./study.cgi?study_id=phs000286) JHS Cohort. Individual level phenotype data and molecular data for all JHS Cohort top-level study and sub-study are available by requesting Authorized Access to the NHLBI JHS Cohort [phs000286](http://./study.cgi?study_id=phs000286) study.

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](https://www.nhlbi.nih.gov/science/framingham-heart-study-fhs) (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.

With these discoveries came the unanticipated realization of considerable gender and ethnic disparities in the prevalence of cardiovascular risk factors, clinically overt CVD, and CVD-related mortality. White women scored lowest in each of these categories, and black men scored highest. To understand and address these disparities, additional cohorts were designed with specified ethnic and racial demographics. One of these, the [Jackson Heart Study](https://www.jacksonheartstudy.org/) (JHS), extends and expands a minority cohort living in Jackson, MS and initially identified within an earlier population-based study (The [Atherosclerosis Risk in Communities](https://www.nhlbi.nih.gov/science/atherosclerosis-risk-communities-aric-study); ARIC). Between 2000-2004 the JHS has enrolled and conducted clinical examinations to determine the prevalence of cardiovascular risk factors and disease in over 5300 subjects. The JHS cohort resembles the recent FHS Offspring examination 6 cohort (JHS: 1907 men, 3395 women; mean age 55 years; FHS Offspring: 1647 men, 1866 women; mean age 59 years), however the FHS cohort contains predominantly white Americans (›95%) of European ancestry while the JHS cohort contains 100% African Americans.

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 JHS. This study includes the generation of deep coverage targeted re-sequencing and variant identification for 219 genes in the [Jackson Heart Study](https://www.jacksonheartstudy.org/) sample collection.