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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 Amish Complex Disease Research Program includes a set of large community-based studies focused largely on cardiometabolic health carried out in the Old Order Amish (OOA) community of Lancaster, Pennsylvania ( The OOA population of Lancaster County, PA immigrated to the Colonies from Western Europe in the early 1700's. There are now over 30,000 OOA individuals in the Lancaster area, nearly all of whom can trace their ancestry back 12-14 generations to approximately 700 founders. Investigators at the University of Maryland School of Medicine have been studying the genetic determinants of cardiometabolic health in this population since 1993. To date, over 7,000 Amish adults have participated in one or more of our studies.

Due to their ancestral history, the OOA may be enriched for rare variants that arose in the population from a single founder (or small number of founders) and propagated through genetic drift. Many of these variants have large effect sizes and identifying them can lead to new biological insights about health and disease. The parent study for this WGS project provides one (of multiple) examples. In our parent study, we identified through a genome-wide association analysis a haplotype that was highly enriched in the OOA that is associated with very high LDL-cholesterol levels. At the present time, the identity of the causative SNP - and even the implicated gene - is not known because the associated haplotype contains numerous genes, none of which are obvious lipid candidate genes. A major goal of the WGS that will be obtained through the NHLBI TOPMed Consortium will be to identify functional variants that underlie some of the large effect associations observed in this unique population.

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

Subjects included in this sequencing sample were from the Amish HAPI Heart Study and the Amish Longevity Study. Participants from these studies were relatively healthy subjects recruited from the Amish community of Lancaster County, PA. Individuals aged 20 years and older were eligible to participate in the HAPI Heart Study along with their age-eligible family members. Amish Longevity Study subjects included long-lived probands aged 90 years or older, their offspring, and spouses of their offspring. HAPI Study exclusion criteria included pregnancy or postpartum < 6 months, high blood pressure (< 180 mmHg SBP or > 105 mmHg DBP), current use of prescription medications that could not safely or willingly discontinued, coexisting malignancy, serum creatinine > 2.0 mg/dL, elevated liver enzymes (AST or ALT > 2X upper limit of normal), hematocrit < 32%, or abnormal TSH (< 0.4 or > 5.5 mIU/L).

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Illumina HiSeq X Ten N/A N/A Sequencing was performed at the Broad Institute of MIT and Harvard.
Study History

Name of grants: Genome-wide search for CVD gene-environment interactions
Agency number: NIH/NHLBI, U01 HL072515
PI: Alan R. Shuldiner, MD
Dates: 2002 - 2010
Specific aims: The goal of this project is to identify genes influencing response to four short-term interventions influencing cardiovascular function in the Amish.

Name of grants: Identification of longevity genes in founder populations
Agency number: NIH/NIA, R01 AG18728
PI: Alan R. Shuldiner, MD
Dates: 2001 - 2006
Specific aims: The goal of this project is to identify genes associated with longevity and longevity-related traits in the Amish.

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