R01HL168174

Integrative genomic and functional genomic studies to connect variant to function for CAD GWAS loci - project summary

Atherosclerotic coronary artery disease (CAD) remains the leading cause of death globally, despite effective therapies for many known risk factors. The majority of CAD loci identified by genome-wide association studies (GWAS) are not associated with traditional risk factors, providing opportunities to discover novel mechanisms and therapies. Encouragingly, many new therapies targeting causal genes and pathways inspired by GWASs have received approval or fared favorably in clinical trials.

Despite the success, the bottleneck remains the lack of experimental studies systematically linking CAD variants to the causal genes and pathways at scale in a cell type-specific manner. To overcome these barriers and define tissue/cell type-specific contribution to the genetic predisposition of CAD risks, we leverage the STARNET eQTL data in nine CAD-relevant tissue/cell types from >1300 subjects and public eQTL data of immune and vascular cells.

Aim 1 will apply advanced computational pipelines to nominate candidate causal CAD variants, cis-regulatory elements (CREs), and their target genes and related pathways at CAD loci in CAD-relevant tissue and cell types, providing tissue/cell type-specific mechanistic and therapeutic insights for CAD. Initial analysis supports that ~30% CAD risk loci are most strongly associated with eQTLs in macrophages or foamy macrophages compared with the other seven tissues in STARNET data. This is in line with the major role of circulating monocyte-derived macrophages in driving atherosclerosis.

Leveraging the rich functional genomic datasets available for monocytes/macrophages, Aim 2 will apply mid-throughput functional assays, including single-cell CRISPR screening, massively parallel reporter assay, and arrayed knockout or overexpression cellular assays, to experimentally define the genetic contributions of monocytes/macrophages to CAD by connecting variants to genes and phenotypic roles, and build machine learning models predicting functional CREs and their target genes.

Our study addresses unmet needs in the functional follow-up of CAD GWASs by performing integrative genomic analysis of CAD loci at an unprecedented scale, experimentally connecting variant to function in cell types critical for the genetic predisposition of CAD, building machine learning models for predicting functional CREs and their target genes for improved prioritization workflow, and providing a generalizable framework for extended discoveries in other CAD-relevant cell types.

With the MPI's expertise in statistical genetics, machine learning, macrophage biology, and functional genomics, our study has significant and broad impacts by providing (1) novel insights into tissue/cell type-specific contributions to the genetic predisposition of CAD that inform new biological mechanisms and therapeutic targets; (2) a catalog of phenotypically tested target genes highly likely to be causal for CAD, allowing immediate refocus to the most promising targets for accelerated translation, and (3) an innovative computational and experimental framework for systematic variant-to-function discoveries.

The Trustees Of Columbia University In The City Of New York

THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. 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]

New York, New York 100323720 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 92% from $1,604,946 to $3,082,334.