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Integrative Approaches to Identifying Function and Clinical Significance of Adiposity Susceptibility Genes

Award Number: R01DK122503
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Integrative Approaches to Identifying Function and Clinical Significance of Adiposity Susceptibility Genes - SUMMARY In 2019, ~100 million Americans were obese, fueling increases in obesity-related morbidity, mortality, and health care costs, largely from cardiometabolic diseases (CMD). Large scale genetic studies have laid the foundation for many downstream investigations into the pathogenesis of disease and the translation of this information into public health applications. Over the last decade genome-wide association studies (GWAS) have substantially improved our understanding of the genetic architecture of obesity related traits. The potential of these study findings cannot be overstated for elucidating the biological or pathophysiological underpinnings of obesity and its costly morbidities. Although GWAS on common variants have made strides in identifying > 1,000 signals for obesity related traits, these studies are inherently limited without further translation into more actionable findings. In this proposal, we will narrow association signals and map causal genes and pathways underlying known obesity risk loci by applying innovative methods to integrate multiple OMICs (genOMICs, epigenOMICs, transcriptOMICs and metabolOMICs). Additionally, we will explore the clinical relevance of obesity susceptibility variants, genes, and pathways in a large BioBank linked to electronic health records (EHR) to validate expected phenotypic associations and reveal novel phenotypic associations. Finally, we will conduct in vitro functional studies of key variants and genes in physiologically relevant cells to reveal putative regulatory mechanisms of variants and effects on metabolites and thus the underlying mechanisms critical to obesity pathogenesis. Thus, in this proposal we leverage collaborations in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), TransOMICs for Precision Medicine (TOPMed) Program, the Genome Sequencing Project (GSP), and the EHR database from the Geisinger MyCODE Community Health Initiative study (MyCode) to narrow in on genes underlying GWAS signals, perform clinical characterization, and conduct in vitro functional studies to characterize the molecular underpinnings and biological mechanisms of obesity-risk loci. Our approach will substantially move the field away from tag variants and loci to causal variants, genes, and mechanisms. We anticipate that this work will generate fundamental and important insights into the underlying etiology of obesity and ultimately point the way forward towards prevention and treatment.


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 = $857,714 )
2026	2026	GEISINGER CLINIC	100 N ACADEMY AVE # MC4970	DANVILLE	PA	17822	MONTOUR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	8/28/2026	COMPETING CONTINUATION	$857,714
2026	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/25/2025	NON-COMPETING CONTINUATION	-$10,826
2026	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	9/1/2026	NON-COMPETING CONTINUATION	$10,826
														Subtotal = $857,714

Issue Date FY: 2024 ( Subtotal = $640,718 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/19/2024	NON-COMPETING CONTINUATION	$640,718
														Subtotal = $640,718

Issue Date FY: 2023 ( Subtotal = $672,571 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$672,571
														Subtotal = $672,571

Issue Date FY: 2022 ( Subtotal = $785,674 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/8/2022	NON-COMPETING CONTINUATION	$677,336
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/14/2022	SUPPLEMENT FOR EXPANSION	$108,338
														Subtotal = $785,674

Issue Date FY: 2021 ( Subtotal = $792,360 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/24/2021	SUPPLEMENT FOR EXPANSION	$108,338
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/28/2021	NON-COMPETING CONTINUATION	$684,022
2021	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/12/2020	NEW	$0
														Subtotal = $792,360

Issue Date FY: 2020 ( Subtotal = $732,482 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/21/2020	NEW	$732,482
														Subtotal = $732,482

Grand Total All Awards = $4,481,519

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Integrative Approaches to Identifying Function and Clinical Significance of Adiposity Susceptibility Genes

Award Number: R01DK122503

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/22/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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