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Study Description

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. Two genotype call sets derived from WGS are now available, one called Freeze 4 (GRCh37) and another called Freeze 5b (GRCh38), with largely overlapping sample sets. Information about how to identify other TOPMed WGS accessions for cross-study analysis, as well as descriptions of TOPMed methods of data acquisition, data processing and quality control, are provided in the accompanying documents, "TOPMed Whole Genome Sequencing Project - Freeze 4, Phase 1" and "TOPMed Whole Genome Sequencing Project - Freeze 5b, Phases 1 and 2". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

The Cleveland Family Study (CFS) is one cohort involved in the WGS project. The CFS was designed to provide fundamental epidemiological data on genetic and non-genetic risk factors for sleep disordered breathing (SDB). In brief, the CFS is a family-based study that enrolled a total of 2284 individuals from 361 families between 1990 and 2006. The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first degree relatives, spouses and available second degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first degree relatives. Each exam, occurring at approximately 4 year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in the participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. The GCRC exam (n=735 selected individuals) included more comprehensive phenotype data on a focused subsample of the larger cohort, to permit linking SDB phenotypes with cardio-metabolic phenotypes, with an interest in identifying genetic loci that are associated with these related phenotypes. In this last round of data collection, a subset of 735 individuals was selected based on expected genetic informativity by choosing pedigrees where siblings had extremes of the apnea hypopnea index (AHI). Participants underwent detailed phenotyping including laboratory polysomnography (PSG), ECG, spirometry, nasal and oral acoustic reflectometry, vigilance testing, and blood and urine collection before and after sleep and after an oral glucose tolerance test. A wide range of biochemical measures of inflammation and metabolism were assayed by a Core Laboratory at the University of Vermont.

994 individuals were sequenced as part of TOPMed Phase 1, including 507 African-Americans and 487 European-Americans. Among the sequenced individuals, 156 were probands with diagnosed sleep apnea, an additional 706 were members of families with probands, and 132 were from neighborhood control families.

  • Please note: Phenotype and pedigree data are available through "NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)", phs000284.
  • This second study release makes available VCF files derived from sequence aligned to genome build 38, in addition to those aligned to build 37 and available through study version 1. The samples in the b38 vs b37 VCF may also differ.

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

CFS Cohort Study

Inclusion Criteria: Cases were probands with laboratory-diagnosed obstructive sleep apnea (AHI > 15 or treated with CPAP). All cases and their first degree and selective second degree relatives and spouses comprised the "case family" sample.

Control probands were selected as a neighbor of the case proband. Their first degree relatives and spouses comprised the control family sample.

Exclusion criteria for the CFS cohort study: Inability to provide informed consent; no family relationship with cases or controls. Additional exclusion criteria for cases were known congenital disorder associated with sleep apnea.

CFS TOPMed Whole-Genome Sequencing Study

Inclusion Criteria: We prioritized individuals for participation based on the availability of phenotype data on sleep apnea and availability of DNA.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Illumina HiSeq X Ten N/A N/A Sequencing was performed at the Northwest Genomics Center at the University of Washington.
Study History

The Cleveland Family Study contains longitudinal data (multiple observations per person). Exam visits occurred as many as 4 times over a 15 year time interval. New participants joined the study during subsequent waves of data collection, thus data are available from one to four exams per participant. The variable named VISIT denotes the type of visit and are labeled as VISIT #1 (1990-2001), VISIT #2 (1996-2001), VISIT #3 (1999-2001) and VISIT #5 (2001-2005) (there is no VISIT #4). These visits did not occur in "waves", instead they reflect which visit number was recorded. Recruitment was rolling, thus some individuals had a first visit (VISIT = 1) after others had a second or third visit (VISIT = 2 or 3).

The first 3 visits occurred in participants' homes. Individuals who participated in visits 2 and 3 included as many participants who were available for examination from a prior visit. There were also additional family members and new minority families recruited later and recorded as visit 1 or 5, depending on type of data collected. Visit 5 occurred in a dedicated clinical research facility (GCRU). This visit targeted minority families and families in whom a prior microsatellite exam had been conducted (selected for genetic informativity). Data collection for visit 5 was more comprehensive - it generally included prior measurements made as well as more detailed biochemical data, ECGs, endothelial function, and sleep staging data. Thus, the data from VISIT = 5 accounts for the most recent visit for data collected on individuals in the Cleveland Family Study and represents the most complete data collection but only includes data for 735 participants.

Selected publications
Diseases/Traits Related to Study (MESH terms)
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