Discovery and characterization of rare variant effects in dilated cardiomyopathy via large-scale biobank analysis

Active Project Grant Awarded Last action

Award ID
R01HL167509
Recipient
Awarding agency
Obligated
$5,507,451

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 87% complete
Place of performance
Forest Hills, TN 37215, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Dilated cardiomyopathy (DCM) affects up to 1:250 individuals and is responsible for ~40% of cardiac transplants. Guidelines recommend genetic testing in DCM probands to help establish diagnosis, guide medical care, inform risk stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of patients, ~30-40% of tests return variants of uncertain significance (VUS), and a modest number of genes have adequate genotype-phenotype data to inform medical management. In this proposal we address 4 gaps in DCM research: 1) most data are from individuals of european ancestry referred for genetic testing, creating bias in estimates of the contribution, penetrance, and phenotype in the broader clinical and community population. 2) most established DCM genes have insufficient genotype-phenotype data to inform gene-specific clinical management. 3) the evidence for most candidate genes is equivocal due to lack of study in cohorts sufficiently large to evaluate pathogenicity. 4) some disease loci likely remain undiscovered because gwas and linkage approaches used in prior studies are not well-powered for diseases, such as DCM, with variable age of onset, both high genetic and allelic heterogeneity, and incomplete penetrance. We will address these fundamental knowledge gaps using innovative genetic methods and a novel, large-scale DCM research platform that includes harmonized phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from 5 large biobanks comprising ~1M participants and >10,000 DCM cases. Specifically, we propose to use rare variant and IBD- based methods to: aim 1) define the contribution and phenotypic manifestations of established disease genes in multiple diverse, non-referral DCM populations; aim 2) assess the pathogenicity of candidate DCM genes with equivocal evidence and establish a novel platform to evaluate VUS in established genes; and aim 3: discover novel DCM genes via IBD mapping and rare variant association within and across biobanks at scale. To balance the innovation of these aims, we present compelling preliminary data demonstrating the feasibility of our approaches which identified a cluster of distantly related individuals harboring a common pathogenic variant in RBM20. We anticipate these analyses will substantially expand our understanding of the genetic factors underlying DCM risk and their clinical manifestations. Once established, our platform will support future clinical and genetic research and advance the long-term goal of implementing targeted interventions at the clinic and population level to reduce the burden of DCM for all patients.

Transactions

Action Obligated Date
Amendment $46,200
Amendment $653,208
Amendment $653,208
Amendment $46,200
Amendment $46,200
Amendment $46,200
Amendment $599,421
Amendment $599,421
Amendment $599,421
Amendment $679,562
Amendment $769,205
Original award $769,205
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Subawards

Subrecipient Amount Awarded
University College London Discovery and Characterization of Rare Variant Effects in Dilated Cardiomyopathy via Large-Scale Biobank Analysis $46,200
The Univeristy Of Texas M.d. Anderson Cancer Center $65,404
Geisinger Clinic $86,017
University College London $46,200
University College London -$121,856
Geisinger Clinic $32,918
The Univeristy Of Texas M.d. Anderson Cancer Center $95,580
University College London $84,985
Geisinger Clinic $78,324
The Univeristy Of Texas M.d. Anderson Cancer Center $62,972
University College London $79,928
Show all 11

Quick answers

Who received award R01HL167509?

R01HL167509 was awarded to Vanderbilt University Medical Center by National Heart Lung and Blood Institute (National Institutes of Health) on May 15, 2023.

How much is award R01HL167509 worth?

$5,507,451 has been obligated on R01HL167509.

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