TOPMed Program

TOPMed Program
Name	TOPMed Program
Established	2014
Founder	National Heart, Lung, and Blood Institute
Location	United States

Contents

TOPMed Program

The Trans-Omics for Precision Medicine (TOPMed) Program is a large-scale initiative led by the National Heart, Lung, and Blood Institute to accelerate research on cardiovascular disease, pulmonary disease, and related conditions through whole-genome sequencing and integrative omics. TOPMed brings together investigators from institutions such as the Broad Institute, University of Washington, Baylor College of Medicine, Harvard Medical School, and consortia including the Framingham Heart Study, the Jackson Heart Study, and the Multi-Ethnic Study of Atherosclerosis to create a shared resource for genomic, phenotypic, and clinical data. The program integrates efforts across agencies and partners such as the National Institutes of Health, the National Cancer Institute, and the All of Us Research Program.

Overview

TOPMed is an NIH-funded research effort organized to generate high-quality whole-genome sequences, transcriptomes, methylomes, and other omics data linked to richly phenotyped cohorts. It coordinates data generation at centers including the New York Genome Center, Broad Institute, and University of Washington Center for Mendelian Genomics while partnering with long-standing cohort studies such as the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Women's Health Initiative. The program supports computational infrastructure like the Database of Genotypes and Phenotypes and cloud platforms used by groups such as DNAnexus and Amazon Web Services under NIH data policies.

TOPMed's objectives include improving understanding of genetic architecture for coronary artery disease, chronic obstructive pulmonary disease, atrial fibrillation, and other conditions by generating deep sequencing data across ancestries represented in studies like the Hispanic Community Health Study/Study of Latinos and the Jackson Heart Study. It aims to enable discovery of rare variant associations identified in datasets linked to clinical trials like Systolic Blood Pressure Intervention Trial and observational studies like the Framingham Heart Study. The program seeks to enhance methods development via collaborations with groups such as the American Heart Association, the International HapMap Project, and the 1000 Genomes Project.

TOPMed aggregates samples from dozens of cohorts spanning population-based studies, disease-focused consortia, and family-based investigations. Major contributing studies include the Framingham Heart Study, the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, the Atherosclerosis Risk in Communities Study, the Women's Health Initiative, and the Hispanic Community Health Study/Study of Latinos. Disease-specific consortia such as the CHARGE Consortium and the CARDIoGRAMplusC4D Consortium participate alongside clinical networks like NICHD Neonatal Research Network and investigators from institutions including Johns Hopkins University, University of Michigan, Columbia University, Stanford University, Yale University, and University of California, San Francisco. Samples include blood-derived DNA, RNA, and clinical phenotypes gathered under protocols influenced by frameworks like the Common Rule.

Sequencing in TOPMed uses high-coverage whole-genome sequencing platforms from providers such as Illumina and alternative technologies including long-read platforms like Pacific Biosciences and Oxford Nanopore Technologies for targeted projects. Data types include whole-genome sequence calls, RNA-seq, DNA methylation arrays, proteomics assayed with mass spectrometry methods developed by groups at Broad Institute, and metabolomics contributed by labs at Massachusetts General Hospital. Variant calling pipelines draw on tools and standards from projects like the Genome Analysis Toolkit and practices from the 1000 Genomes Project and Exome Aggregation Consortium. TOPMed's harmonization efforts echo methods used in the Human Genome Project and the ENCODE Project for quality control and annotation.

TOPMed data are managed in accordance with NIH data-sharing policies and deposited in controlled-access repositories such as the Database of Genotypes and Phenotypes overseen by the National Center for Biotechnology Information. Access protocols align with standards from the FTPS, data use agreements used by the All of Us Research Program, and institutional review frameworks applied at centers like Massachusetts Institute of Technology and University of Washington. Consent and data use restrictions reflect templates from the Common Rule and guidance from bodies including the Presidential Commission for the Study of Bioethical Issues and the National Academies of Sciences, Engineering, and Medicine. Cloud-based analytic platforms hosted by partners such as Amazon Web Services and Google Cloud Platform facilitate secure research collaborations with compliance comparable to systems used by the 1000 Genomes Project.

TOPMed has contributed to discovery of rare and structural variant associations for conditions such as atrial fibrillation, coronary artery disease, heart failure, and chronic obstructive pulmonary disease, complementing results from consortia like CARDIoGRAMplusC4D and CHARGE. Findings have informed polygenic risk assessment methods related to work by groups at Harvard Medical School, Broad Institute, and Stanford University and have refined allele frequency catalogs across ancestries similar to resources from the 1000 Genomes Project and gnomAD. TOPMed-enabled studies improved imputation reference panels used in analyses by teams at University of Michigan and Johns Hopkins University and have supported translational efforts in pharmacogenomics tied to institutions like Mayo Clinic and Vanderbilt University Medical Center.

ELSI work within TOPMed addresses consent, return of results, privacy, and equitable representation, drawing on ethics scholarship associated with Presidential Commission for the Study of Bioethical Issues, the Belmont Report, and policy frameworks from the National Institutes of Health. Engagement with diverse communities such as participants from the Jackson Heart Study and the Hispanic Community Health Study/Study of Latinos informs practices similar to community-engaged research at University of California, San Francisco and Johns Hopkins University. Legal considerations interact with statutes and precedents involving Health Insurance Portability and Accountability Act protections and intellectual property issues considered in contexts like the Bayh-Dole Act. TOPMed collaborations also interface with patient advocacy organizations such as the American Heart Association and clinical guideline bodies including the American College of Cardiology to translate discoveries responsibly.

Category:Genomics Category:Biomedical research programs