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Study Description

This substudy phs000401 Framingham ESP Heart-GO contains exome sequence data and harmonized phenotype variables, produced as part of NHLBI's GO-ESP project. Summary level phenotypes for the Framingham Cohort study participants can be viewed at the top-level study page 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.

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.

HeartGO is a consortium of six well-phenotyped NHLBI cohorts: Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Together, for the GO-ESP, these cohorts have provided DNA and phenotype datasets from a diverse cohort of individuals of African and Caucasian ancestry to be made available for use by qualified investigators in dbGaP. HeartGO investigators will conduct genotype-phenotype analyses for phenotypes related not only to heart disease but with other variables that will be contributed to dbGaP. The HeartGO dataset provides investigators with genotype-phenotype analytic opportunities for traits not only related to heart disease but also associated with ancillary variables that will be contributed to dbGaP, including disease endpoints, risk factors, biomarkers, and subclinical disease measures.

The phenotypes planned for investigation as part of the GO-ESP HeartGO project include five primary phenotypes for which initial ascertainment of samples for exome sequencing were made (early-onset myocardial infarction (EOMI), low density lipoprotein (LDL) cholesterol, body mass index/type 2 diabetes (BMI/T2D), blood pressure and ischemic stroke) and a randomly ascertained common comparison group with extensive phenotyping (deeply phenotyped reference, DPR). Additional phenotypes available on these selected samples permitted a large array of additional analyses to be performed. These secondary phenotypes account for ~80 outcomes from both qualitative and quantitative traits. Results of the proposed analyses as well as relevant replication/follow-up analyses will be reported in peer-reviewed journals.

This study phs000401 contains the Framingham Heart Study (FHS) subset of GO-ESP/Heart-GO. Additional GO-ESP data is also available via dbGaP.

  • Study Weblink: NHLBI GO-ESP
  • Study Types: Case-Cohort, Case-Control, Cohort, Affected Sib Pairs, Exome Sequencing
  • dbGaP estimated ancestry components using GRAF-pop
  • Number of study subjects that have individual level data available through Authorized Access: 462

Authorized Access
Publicly Available Data (Public ftp)

Note: Access to publicly available data is available on the public ftp site for study phs000007.v30.p11.

Study Inclusion/Exclusion Criteria

The following are the inclusion/exclusion criteria across the HeartGO consortia phenotype groups; each HeartGO cohort was represented in one or more of these phenotype groups.

Early-Onset MI (EOMI):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 200 cases with early-onset myocardial infarction (MI) and 200 participants with absence of MI despite extreme Framingham Risk Score (FRS).
Inclusion of individuals with consent and DNA available; for cases, the participant data includes study adjudication of reported MI and onset prior to age 45y (men) or 55y (women); for comparison (non-MI) participants, there must be data to calculate the Framingham Risk Score (FRS; age, sex, total cholesterol, HDL cholesterol, smoking status, systolic blood pressure, blood pressure medications), with age greater than 50y (men) or 60y (women).
Exclusion of participants with prevalent or incident CVD; cases with self-reported MI but without adjudication of clinical data.

LDL Cholesterol (LDL):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 100 participants with extremely low LDL and 100 participants with extremely high LDL, after adjustment for age, sex, lipid medication status.
Inclusion requires consent and available DNA, and presence of the following variables: race, sex, LDL measurement (baseline and any additional), age at LDL measurement, lipid-lowering medication status, and not being sequenced for other phenotypes.

Blood Pressure (BP):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 200 participants with extremely low residual systolic and diastolic blood pressure and 200 participants with extremely high residual systolic and diastolic blood pressure, after adjustment for age, sex, medication status and BMI.
Inclusion requires consent and available DNA, and presence of the following variables: race, sex, systolic blood pressure (SBP), diastolic blood pressure (DBP), age, hypertension medication status and BMI.
Exclusion of participants (or data) with age > 69 yr, prevalent MI, heart failure or BMI > 4SD at any exam but only for that exam (for those participants with multiple measurements); for selection of extreme low BP individuals, exclude those individuals who are on antihypertensive treatment or who are unknown to be on antihypertensive treatment.

Ischemic Stroke (STROKE):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 250 participants with early onset (less than 65y) or positive family history of ischemic stroke. These cases will be compared with the deeply phenotyped reference (DPR) sample.
Inclusion requires consent and available DNA, and available documentation that the stroke is ischemic and has been adjudicated with characteristics of likely etiology (subtyping). Required variables include race, sex, family history of stroke, and age at stroke. Only participants with a positive family history of stroke and/or diagnosed prior to 65 y will be included. Stroke subtypes included for study include small vessel occlusion/lacunar and large artery atherosclerosis/atherosclerotic (more specifically, non-lacunar and non-cardioembolic).
Exclusion of participants includes those with absence of subtyping (based on TOAST, SHEP or equivalent criteria). Participants will be excluded if unknown or undefined stroke subtype; cardioembolic stroke subtype is also excluded.

Deeply Phenotyped Reference (DPR):
Initial Study Design: Within each of the two ethnic groups (whites and blacks), selection of participants not previously ascertained for primary phenotypes to be used as a common comparison group (e.g., in a case-cohort analysis). These subjects will consist of ~1000 whites and ~500 blacks with extensive phenotypic data, available DNA and documentation of approval for deposition into dbGaP. Within HeartGO, the ascertainment of samples was based upon the size of the available sample in each of the orginal cohorts (e.g., ARIC provided the most samples as it was the largest cohort, JHS provided only blacks while FHS provided only whites).

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Exome Sequencing Illumina Genome Analyzer IIX N/A N/A
Exome Sequencing Illumina HiSeq 2000 N/A N/A
Study History

The Framingham Heart Study (FHS) began in 1948 by recruiting an original cohort of 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke. Since that time the FHS has added an Offspring Cohort in 1971, an Omni Cohort in 1994, a Third Generation Cohort in 2002, a New Offspring Spouse Cohort in 2003, and a Second Generation Omni Cohort in 2003. Over the years, careful monitoring of the FHS population has led to the identification of major CVD risk factors, as well as valuable information on the effects of these factors such as blood pressure, blood triglyceride and cholesterol levels, age, gender, and psychosocial issues. Risk factors for other physiological conditions such as dementia have been and continue to be investigated. In addition, the relationships between physical traits and genetic patterns are being studied. For GO-ESP, a total of 499 FHS participants were selected for exome sequencing and sent to both sequencing centers for processing. A total of 493 samples passed Q/C metrics, 475 (96%) provided finished sequence data, and 464 individuals are represented in GO-ESP data in dbGaP.

Selected publications
Diseases/Traits Related to Study (MESH terms)
Authorized Data Access Requests
Study Attribution