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Identifying Cis-Regulatory Variants, Genes, and Regulatory Networks Underlying QT Interval Variation

Award Number: R01HL158901
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Identifying Cis-Regulatory Variants, Genes, and Regulatory Networks Underlying QT Interval Variation - PROJECT SUMMARY/ABSTRACT Electrocardiographic QT interval, an index of ventricular repolarization, is a clinically relevant heritable quantitative trait associated with risk for cardiac arrhythmias and sudden cardiac death (SCD). Genetic studies in subjects with rare Mendelian long- and short-QT syndromes have identified rare, severe coding mutations in ~20 genes encoding voltage-gated ion channels, transporters and associated proteins that regulate cardiac action potential duration (APD) or excitation-contraction (EC) coupling. Prevalence of coding polymorphisms in these genes affecting population repolarization variability is extremely low. In contrast, genome-wide association studies (GWAS) of QT interval in the general population have identified common, noncoding variants at nearly three dozen loci, collectively explaining ~20% of the additive variance. Nearly half of these GWAS loci harbor genes known to regulate cardiac APD or EC coupling, thus serving as the likely causal genes. Nonetheless, the identities of the actual causal genes and molecular mechanisms underlying associations with the common and, largely noncoding variants at these loci, remain unknown. Moreover, a large fraction (~80%) of the additive variance remains unidentified. Leveraging information on known genes, in the proposed studies we will address these gaps in our knowledge based on the hypotheses that a) multiple common variants that impact the activities of several cis-regulatory elements (CREs) underlie a GWAS signal by collectively influencing the expression of a target gene, and b) genes underlying specific or similar diseases/traits are often functionally related, and that functionally related genes often belong to gene regulatory networks (GRNs), members of which are co-regulated. We aim to functionally characterize selected QT interval GWAS loci with a priori evidence for likely causal genes as well as extend gene discovery by assessing the impacts of perturbing the expression of known QT interval genes on their GRNs. Our specific aims are: (1) identification of functional CRE variants at selected QT interval GWAS loci by evaluating all trait-associated common variants overlapping cardiac open chromatin regions in high-throughput reporter assays in mouse cardiomyocyte HL1 cells; and to link CREs and their variants to putative target genes based on expression quantitative trait locus and chromatin contact analyses in human adult left ventricle tissue and induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs); and (2) performing CRISPR activation/interference-based expression perturbations of selected QT interval genes in neonatal rat ventricular myocytes (NRVMs), and assessing transcriptome-wide effects to identify candidate co-regulated gene sets; evaluating the co-regulated gene sets for enrichment in sub-threshold GWAS loci; overlapping co-regulated genes with QT GWAS loci to identify likely causal genes; and assessing the impact of perturbing expression of newly identified genes on cellular electrophysiology in NRVMs and hiPSC-CMs. Together, the proposed studies are expected to lead to a better understanding of the molecular mechanisms underlying QT interval variation and SCD risk, and serve as a model for functional characterization of GWAS loci of complex diseases and traits.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	4	2/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $545,240 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	$490,717
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	001	4	7/1/2025	NON-COMPETING CONTINUATION	$54,523
														Subtotal = $545,240

Issue Date FY: 2024 ( Subtotal = $534,335 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$43,618
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	3	4/1/2024	NON-COMPETING CONTINUATION	$490,717
														Subtotal = $534,335

Issue Date FY: 2023 ( Subtotal = $521,840 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	2	3/28/2023	NON-COMPETING CONTINUATION	$521,840
														Subtotal = $521,840

Issue Date FY: 2022 ( Subtotal = $518,231 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	1	4/20/2022	NEW	$518,231
														Subtotal = $518,231

Grand Total All Awards = $2,119,646

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Identifying Cis-Regulatory Variants, Genes, and Regulatory Networks Underlying QT Interval Variation

Award Number: R01HL158901

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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