NHLBI TOPMed: MESA and MESA Family AA-CAC

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, Freeze 8 (GRCh38) and Freeze 9b (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 8, Phases 1-4" and "TOPMed Whole Genome Sequencing Project - Freeze 9b, Phases 1-4". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent.

Comprehensive phenotypic and pedigree data for MESA study participants are available through dbGaP entry phs000209.

MESA

Participants were recruited from six field centers across the United States: Wake Forest University, Columbia University, Johns Hopkins University, University of Minnesota, Northwestern University and University of California - Los Angeles. Each participant received an extensive physical exam and determination of coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery, lower extremity vascular insufficiency, arterial wave forms, electrocardiographic (ECG) measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Selected repetition of subclinical disease measures and risk factors at follow-up visits allows study of the progression of disease. Blood samples have been assayed for putative biochemical risk factors and stored for case-control studies. DNA has been extracted and lymphocytes cryopreserved (for possible immortalization) for study of candidate genes and possibly, genome-wide scanning, expression, and other genetic techniques. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality.

In addition to the six Field Centers, MESA involves a Coordinating Center, a Central Laboratory, and Central Reading Centers for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound, and Electrocardiography (ECG). Protocol development, staff training, and pilot testing were performed in the first 18 months of the study. The first examination took place over two years, from July 2000 - July 2002. It was followed by five examination periods that were 17-20 months in length. Participants have been contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality.

MESA Family

The general goal of the MESA Family Study, an ancillary study to MESA funded by a grant from NHLBI, is to apply modern genetic analysis and genotyping methodologies to delineate the genetic determinants of early atherosclerosis. This is being accomplished by utilizing all the current organizational structures of the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetic Centers at Cedars-Sinai Medical Center and University of Virginia.

In the MESA Family Study, the goal is to locate and identify genes contributing to the genetic risk for cardiovascular disease (CVD), by looking at the early changes of atherosclerosis within families (mainly siblings). 2128 individuals from 594 families, yielding 3,026 sibpairs divided between African Americans and Hispanic-Americans, were recruited by utilizing the existing framework of MESA. MESA Family studied siblings of index subjects from the MESA study and from new sibpair families (with the same demographic characteristics) and is determining the extent of genetic contribution to the variation in coronary calcium (obtained via CT Scan) and carotid artery wall thickness (B-mode ultrasound) in the two largest non-majority U.S. populations. In a small proportion of subjects, parents of MESA index subjects participating in MESA Family were studied but only to have blood drawn for genotyping.

The MESA Family cohort was recruited from the six MESA Field Centers. MESA Family participants underwent the same examination as MESA participants during May 2004 - May 2007. DNA was extracted and lymphocytes immortalized for study of candidate genes, genome-wide linkage scanning, and analyzed for linkage with these subclinical cardiovascular traits. While linkage analysis is the primary approach being used, an additional aspect of the MESA Family Study takes advantage of the existing MESA study population for testing a variety of candidate genes for association with the same subclinical traits. Genotyping and data analysis will occur throughout the study.

• Study Weblinks:
  • MESA
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Family
  • Longitudinal
• dbGaP estimated ancestry using GRAF-pop
• Subject Sample Telemetry Report (SSTR)

A detailed account of inclusion and exclusion criteria for participation in the MESA and MESA Family studies is available through the dbGaP entry phs000209. MESA Selection for TOPMed whole genome sequencing is based on the following algorithm:

Required:

1. MESA Classic participant
2. Consented to MESA Genetics participation and have acceptable DNA as indicated by participation in prior genotyping activities such as MESA SHARe genome wide scan or MESA Exome Chip.
3. Sufficient DNA volume in central lab repository (≥ 40 mcg DNA).

Select top 4,595 according to the following weighted selection criteria with an additional 919 selected as replacements in case there is insufficient DNA quality or quantity (WGS will be completed in 4,595).

Priority Selection (20 point weight towards selection)

1. MESA Family proband [+20 points]

Weighting toward selection criteria:

1. Sibling of MESA Family proband [+1 point]
2. CVD all event or atrial fibrillation event or heart failure event [+1 point]
3. MESA Group 3 (a.k.a. MESA 1000) [+1 point]
4. Baseline chest CT [+1 point]
5. Follow-up chest CT [+1 point]
6. Baseline carotid US [+1 point]
7. Follow-up carotid US [+1 point]
8. Baseline chest MRI [+1 point]
9. Metabolomics/COMBIBio [+1 point]
10. Epigenomics [+1 point]
11. MESA Lung participant with Lung CT [+1 point]
12. MESA Lung Participant with spirometry [+1 point]
13. MESA Sleep PSG [+1 point]
14. Completed Exam 5 and not marked as deceased [+1 point]

There are 3,706 patients with a priority score ≥ 8 calculated using the above noted algorithm, so 889 participants with priority score = 7 were selected at random resulting in 4,595 selected participants (all with priority score ≥ 7 and meeting more than half of the priority criteria).

Participants selected as alternates include the remaining 34 participants with priority score = 7, the remaining 299 participants with either a Lung CT scan or spirometry, the remaining 497 participants with priority score = 6, and 89 randomly selected participants from those with priority score = 5. In total, 5,514 participants are selected for TOPMed whole genome sequencing including the 4,595 participants with the highest priority scores and 919 alternate IDs which includes participants with MESA Lung CT scans or spirometry and those participants with the next highest priority scores.

Participants were not selected if they did not meet the basic criteria of being a MESA Classic participant with consent for genetics participation (or do not have evidence of sufficient DNA quality or volume as evidenced by MESA SHARe participation and having at least 40 mcg DNA in the repository maintained by the central laboratory). Participants with low priority scores also were typically not selected (lowest score was one individual with score = 3 who was selected due to completion of MESA Lung component).

Whole genome sequencing was completed on 4,619 MESA Classic participants

• 4,550 of the originally selected 4,595 MESA Classic participants had TOPMed WGS completed.
• 69 of the alternate selected MESA classic participants had TOPMed WGS completed.

MESA Family Ancillary study also provided DNA samples for TOPMed WGS via the study/designation of "AACAC" (African-American Coronary Artery Calcium consortium study). Sample selection in this case was defined as having consented to MESA Family Ancillary Study (which required genetics consent), not already sequenced as a MESA participant, and having self-reported Black or African-American race.

• Primary Phenotype: Cardiovascular Diseases
• Cardiovascular Risk Factors

• Principal Investigator
  • Jerome I. Rotter, MD. LA BioMed Harbor/UCLA, Los Angeles, CA, USA.
  • Kent D. Taylor, PhD. LA BioMed Harbor/UCLA, Los Angeles, CA, USA.
• Project Officer
  • Lorraine Silsbee. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
• MESA WGS Funding Source
  • 3U54HG003067-13S1. National Institutes of Health, Bethesda, MD, USA.
• MESA AACAC WGS Funding Source
  • HHSN 268201500014C. National Institutes of Health, Bethesda, MD, USA.