Human Medical Sequencing Program and Current Initiatives

Allelic Spectrum in Common Disease

Initiative Rationale

This area would involve sequencing genes implicated in common disorders in large, well-phenotyped cohorts. Potential examples include genes that contribute to blood pressure, type 2 diabetes, epilepsy, and neurodegeneration. The genomic locus encompassing each gene would be completely sequenced in every member of one or more large cohorts of individuals (i.e. thousands), to obtain adequate power, sampled from the full trait distribution, in whom relevant physiological parameters have been accurately measured, perhaps augmented by a reference resource such as HapMap.

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Project Descriptions

Age-related Macular Degeneration
Proposed by Goncalo Abecasis et al., University of Michigan
Sequencing by Washington University in St. Louis

Age-related macular degeneration (AMD) is a degredation of cells in the macula that damages sharp vision in the central visual field and may lead to permanent vision loss. The National Eye Institute states that while middle-age people have about a 2% risk of AMD, individuals older than 75 have around a 30% chance of AMD diagnosis. A study linking the complement factor H gene with AMD has been replicated by several groups (Klein et al. Science 308: 385-389, 2005). Detailed genetic analysis of this region is needed to determine other potentially rare susceptibility haplotypes. This project will sequence the complement factor H gene (OMIM #134370) in about 1,400 mostly Caucasian individuals.

Diabetes and Metabolic Syndrome
Proposed by Michael Boehnke, University of Michigan; and Nelson Freimer, University of California, Los Angeles
Sequencing by Washington University in St. Louis and National Institutes of Health Intramural Sequencing Center

Diabetes is a common metabolic disorder in which defects in the way insulin is produced or acts within the body leads to high levels of blood glucose. The National Institute of Diabetes and Digestive and Kidney Diseases estimated that in 2007 about 23.6 million people in the United States were affected by diabetes. According to the National Heart, Lung, and Blood Institute, metabolic syndrome is a grouping of clinical features that includes: abdominal obesity, high triglyceride level, low HDL cholesterol level, high blood pressure, and high fasting blood glucose. These features can increase the chances of diabetes, heart disease, or stroke. In 2007, about 47 million Americans were characterized with metabolic syndrome based on data from the National Heart, Lung, and Blood Institute. This number is increasing steadily as the prevalence of obesity in adults increases. This project will sequence 113 genes associated with type 2 diabetes in about 1,600 Caucasian individual from the FUSION study and 10 genes associated with metabolic syndrome in about 5,600 Caucasian individuals from the Northern Finland Birth Cohort.

Cardiovascular Disease
Proposed by Christine Seidman, Harvard University
Sequencing by Broad Institute

Cardiovasular disease has a significant impact on the health and mortality rate of Americans. The National Center for Health Statistics reports that it is the highest ranked cause of death in the United States. According to the National Heart, Lung, and Blood Institute, cardiovascular disease is the inability of the heart to function properly. While environmental factors have a large role in the development of cardiovascular disease, investigators have identified many targets for genetic variation that may confer substantial heritable risk for the disease. This project aims to examine the spectrum of allelic variation in about 76 genes that contribute to hypertension, cardiac hypertrophy and dilation, aberrant cardiac electrophysiology, dyslipidemias, and diabetes in over 4000 unrelated subjects from primarily European-American and African-American participants in the Framingham and Jackson Heart Studies.

Tetralogy of Fallot
Proposed by Christine Seidman, Harvard University
Sequencing by Broad Institute

Tetralogy of Fallot is a congenital heart condition that includes a large hole between the lower chambers of the heart (lventricular septal defect), narrowing of pulmonary valve and passageway (stenosis), thickening of the right ventricle (hypertrophy), and a defect in the location of the aorta (overriding aorta). The National Heart, Lung, and Blood Institute reports that about 5 out of every 10,000 babies are affected by the disorder. The only treatment option is to surgically repair the heart. It is a significant cause of stillbirths worldwide. Recent molecular genetic studies of families with dominant transmission of heart malformations have led to the discovery of gene targets that are linked to the disease. This project will sequence about 77 target genes with evidence for linkage to the disease in about 765 individuals.

Proposed by Patrick Sullivan, University of North Carolina, Chapel Hill
Sequencing by Baylor College of Medicine

Approximately 2 millon adults in the US are affected by schizophrenia (Jablensky. Eur Arch. Psychiatry Clin. Neurosci. 250: 274-285, 2000). It has a high economic and quality of life burden because of the necessity for lifelong treatment upon diagnosis. The National Institute of Mental Health summarizes schizophrenia as a severe brain disorder that causes hallucinations and disordered thoughts or movements. At least 12 genes have strong linkage evidence based on family, adoption, and twin studies (Sullivan et al. Arch. Gen. Psy. 60: 1187-1192, 2000). This project will characterize these 12 target genes in 765 individuals involved in the diverse CATIE study.

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Approved Medical Sequencing Projects

Currently, there are no openings for new proposals in this area. However, NHGRI encourages investigators that are interested to contact program staff to discuss potential projects. Please send inquiries to the program contacts listed below.

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Program Contacts

Adam Felsenfeld, Ph.D.
Program Director

Jane Peterson, Ph.D.
Associate Director, Division of Extramural Research

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Last Reviewed: November 15, 2011