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Functional Analysis of T2D Associated Non-coding SNPs

Award Number: U01DK105541
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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Functional Analysis of T2D Associated Non-coding SNPs - DESCRIPTION (provided by applicant): More than 27 million Americans suffer from Type 2 diabetes (T2D). GWAS have identified 128 lead SNPs associated with T2D and/or fasting hyperglycemia, but little is known about how these variants contribute to T2D pathogenesis. A major challenge in functionally characterizing variants found in GWAS is that each lead SNP directly associated with a trait is in LD with a collection of additional variants, and thus identifying the precise variant(s) underlying the association requires extensive computational and experimental analyses. Additionally, the majority of the associated SNPs are located within non-coding regions, where inferring functional consequences of sequence variants remains challenging. Finally, when associated SNPs are identified as candidate regulatory variants, functional testing is frequently hampered by a lack of appropriate experimental models. To address these challenges we have assembled a team of highly accomplished researchers in genomics (Frazer), epigenomics (Ren) and T2D biology (Sander). We propose to combine state-of-the-field computational methods, high throughput molecular assays, and disease modeling in human embryonic stem cells to comprehensively annotates T2D GWAS data and test variants for their gene regulatory function. In Aim 1 we will analyze 5,150 whole-genomes for variants in T2D and fasting hyperglycemia GWAS risk-associated loci. We estimate that these analyses will identify ~1,000,000 variants with a MAF > 1% in the intervals of interest. Additionally, we will identify rare variants that are enriched in T2D patients. We estimate that intersecting these data with existing epigenomic datasets will identify ~99,000 variants in putative regulatory elements in T2D-relevant tissues. In Aim 2 we will use three high throughput molecular assays to characterize these 99,000 candidate regulatory variants in T2D-relevant cell types. First, we will carry out massively parallel reporter assays (MPRA) to test the potentia of each SNP-harboring sequence element to act as a transcriptional enhancer, and if so, whether enhancer activity is affected by the candidate variant. Second, we will carry out a high throughput in vitro binding assay (SELEX) to determine whether the candidate variants affect DNA binding of relevant transcription factors. Third, we will predict target genes of the candidate variants using high throughput chromosome conformation capture (Hi-C) assays. In Aim 3, results from Aim 1 and Aim 2 will be integrated to prioritize 20 beta cell-relevant SNPs for functional validation. Key criteria include: (1) the variant resides in an active beta cell enhance, (2) disrupts transcription factor binding, and (3) targets T2D-relevant genes in Hi-C assays. We will validate these variants by (1) genetic engineering of an embryonic stem cell-derived cell model of human beta cells, testing how deletion of the cis-regulatory element or introduction of the risk variant affects target gene expression; (2) genetic engineering of mouse models, testing whether candidate enhancer/target gene pairs control glucose metabolism in vivo. The proposed study will provide key insights into the underpinnings of regulatory variants identified through GWAS in T2D etiology.


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: 2021 ( Subtotal = $0 )
2021	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	10/15/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/1/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $879,348 )
2019	2019	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/26/2019	NON-COMPETING CONTINUATION	$879,348
														Subtotal = $879,348

Issue Date FY: 2018 ( Subtotal = $890,838 )
2018	2018	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	8950 VILLA LA JOLLA DR STE C135	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/13/2018	NON-COMPETING CONTINUATION	$890,838
														Subtotal = $890,838

Issue Date FY: 2017 ( Subtotal = $980,746 )
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/16/2017	NON-COMPETING CONTINUATION	$98,074
2017	2017	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	3262 HOLIDAY CT STE 201	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/27/2017	NON-COMPETING CONTINUATION	$882,672
														Subtotal = $980,746

Issue Date FY: 2016 ( Subtotal = $977,455 )
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/14/2016	SUPPLEMENT FOR EXPANSION	$73,906
2016	2016	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/10/2016	NON-COMPETING CONTINUATION	$903,549
														Subtotal = $977,455

Issue Date FY: 2015 ( Subtotal = $906,961 )
2015	2015	LUDWIG INSTITUTE FOR CANCER RESEARCH LTD	9500 GILMAN DRIVE CMME BLDG	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/15/2015	NEW	$906,961
														Subtotal = $906,961

Grand Total All Awards = $4,635,348

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Functional Analysis of T2D Associated Non-coding SNPs

Award Number: U01DK105541

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 05/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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