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Atlas of Regulatory Variants in Diseases (ARVID)

Award Number: U24HG010856
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Atlas of Regulatory Variants in Diseases (ARVID) - NHGRI U24: ATLAS OF REGULATORY VARIANTS IN DISEASE (ARVID) PROJECT SUMMARY Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) linked to risk of developing specific non-cancerous polygenic diseases, including ischemic heart disease, chronic obstructive pulmonary disease, Alzheimer’s dementia, type 2 diabetes, and ischemic stroke. These disease-linked SNPs concentrate in regulatory DNA active in cell types that may mediate disease risk by modulating genes (eGenes) whose expression levels may be important in pathogenesis. These disease-linked expression SNPs (eSNPs) commonly alter transcription factor (TF) DNA binding motifs, indicating they may affect regulatory DNA activity by changing gene regulator binding. This U24 proposal aims to generate a genomic resource, the Atlas of Regulatory Variants in Disease (ARVID), containing the following 3 broad categories of information: 1) the individual disease-linked human eSNPs with differential gene regulatory function in relevant cell types 2) the target genes (eGenes) that these eSNPs dysregulate and 3) the gene regulators whose DNA association such disease eSNPs alter. First, we will identify the specific functionally altered eSNPs among those linked to index SNPs identified by GWAS in the 5 widespread human diseases noted above using massively parallel reporter assays (MPRA). A resulting subset of 300 top disease risk and non-risk eSNP pairs will then be deeply characterized in isogenic cells generated by gene editing to identify directly and indirectly dysregulated target genes. This effort will produce a Genomic Compendium of a) the disease-linked eSNPs that quantitatively impact regulatory DNA function in disease-relevant cell types and of b) the eGenes for the 300 top disease eSNPs. Second, we will identify the specific gene regulators whose DNA association is altered at the 300 disease risk eSNPs above, compared to matched non-risk alleles. To do this, we will use a live-cell proteomics approach termed DNA Protein Interaction Detection (DAPID). Quantitative mass spectrometry using isobaric tagging will be complemented by quantitative chromatin immunoprecipitation (ChIP) assays using isogenic, disease-relevant cells that differ only at the single eSNP nucleotide of interest. This effort will produce a Proteomic Atlas of differential regulator binding at 300 reference-disease eSNP pairs. This NHGRI U24 will generate a genomic resource defining the DNA variants, target genes, and gene regulators involved in inherited risk for 5 common non-cancerous polygenic human diseases.


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: 2024 ( Subtotal = $652,539 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Human Genome Research	000	5	6/21/2024	NON-COMPETING CONTINUATION	$652,539
														Subtotal = $652,539

Issue Date FY: 2023 ( Subtotal = $666,905 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Human Genome Research	000	4	5/22/2023	NON-COMPETING CONTINUATION	$666,905
														Subtotal = $666,905

Issue Date FY: 2022 ( Subtotal = $662,526 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Human Genome Research	000	3	5/24/2022	NON-COMPETING CONTINUATION	$662,526
														Subtotal = $662,526

Issue Date FY: 2021 ( Subtotal = $657,314 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Human Genome Research	000	2	6/4/2021	NON-COMPETING CONTINUATION	$657,314
														Subtotal = $657,314

Issue Date FY: 2020 ( Subtotal = $650,695 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Human Genome Research	000	1	8/20/2020	NEW	$650,695
														Subtotal = $650,695

Grand Total All Awards = $3,289,979

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Atlas of Regulatory Variants in Diseases (ARVID)

Award Number: U24HG010856

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/20/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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