R01HL164675

Systematically Mapping Variant Effects for Cardiovascular Genes

Cardiovascular diseases are leading global causes of death and disability, presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure, and arrhythmias. They arise from interactions between environmental factors and common and rare genetic variants, including relatively common Mendelian lipid disorders, cardiomyopathies, and arrhythmias that collectively occur in at least 1/100 individuals.

The availability of genetic sequencing is altering clinical management, but a major barrier to the widespread application of this practice is that the function of the vast majority of variants in key cardiovascular disease genes is unknown. Variant effect maps that define function for nearly all missense variants in a target sequence offer a way forward. This project brings together scientists at the forefront of variant effect mapping in diverse cellular systems, illuminating underlying cardiovascular biology, establishing relationships between variant function and human phenotypes, and working with others in multi-institutional collaborations.

Our CardioVar team will generate a comprehensive atlas of variant effect maps for key cardiovascular disease genes.

In Aim 1, we will develop, optimize, and validate a range of high-throughput cellular assays. We will use a range of generalizable (e.g. surface abundance) and bespoke (e.g. electrophysiological, lipoprotein uptake) assays to directly measure variant function in disease-relevant context. Assays will be assessed by their ability to discriminate pathogenic from benign variants.

In Aim 2, we will use in situ targeted mutagenesis or insertion of variant constructs at a safe harbor site to generate pools of cells capturing all single-nucleotide changes in target genes. We will then deploy existing validated assays and those emerging from Aim 1 to generate and validate variant effect maps at scale. Functional scores and uncertainty estimates will be derived and evaluated, both by performance on pathogenic and benign variants and on correlation with discrete and quantitative phenotypes in clinical cohorts.

In Aim 3, we will derive biological and clinical insights from variant effect maps. Discordant cases, where variant scores diverge from clinical annotation, will be further investigated in zebrafish, iPSC-cardiomyocytes, and automated patch clamping systems. Through a combination of hypothesis-driven analysis and machine learning models, we will reveal relationships among variant effects, protein structure, protein function, and human phenotypes.

To optimize use of the atlas, we will provide a portal serving as a variant-centric decision support system for evaluating functional evidence of pathogenicity. We will release variant effect map data pre-publication via MAVEDB (that we co-developed) and share all renewable variant assay reagents.

The CardioVar atlas of missense variant effects, covering key cardiovascular disease genes, will be an essential and interpretable community resource for clinical and mechanistic studies of cardiovascular disease.

Vanderbilt University Medical Center

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Nashville, Tennessee 372152691 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 289% from $2,085,976 to $8,116,228.