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Multi 'Omics Integration and Neurobiological Signatures of Alcohol Use Disorder

Award Number: R01AA027049
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/24/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Multi 'Omics Integration and Neurobiological Signatures of Alcohol Use Disorder - PROJECT SUMMARY/ABSTRACT The goal of the proposed research is to discover neurobiological factors underlying alcohol use disorder (AUD). We will identify genes with AUD-related differences in DNA methylation (DNAm) and RNA expression (RNAexp) in two human brain tissues for AUD (dorsolateral prefrontal cortex [DLPFC] and nucleus accumbens [NAc]), map genetic variants underlying these differences, and conduct large-scale association testing of the regulatory genetic variants with AUD. Our proposed study will entail genome-wide testing, along with targeted testing of the growing number of genetic loci associated with alcohol consumption and AUD. Alcohol is the fourth leading cause of preventable morbidity and mortality in the United States. AUD affects more than 16 million U.S. adults and youths and is highly heritable (50%–60%). Genome-wide association study (GWAS) analyses have identified single nucleotide polymorphisms in or near alcohol dehydrogenase and aldehyde dehydrogenase genes and 80+ other genetic loci for alcohol consumption and/or AUD risk. However, their neurobiological effects are largely unknown. Because complex disease-associated variants are widely observed to be enriched for association with DNAm and RNAexp of nearby genes (cis-methylation and expression quantitative trait loci [cis-meQTLs and cis-eQTLs], respectively), we hypothesize that differential gene regulation by AUD will add knowledge of the neurobiology underlying AUD risk and consequences of alcohol exposure and that mapping the underlying cis-meQTLs and cis-eQTLs in DLPFC and NAc, will distinguish these distinct, yet informative, neurobiological signatures. We propose the following specific aims: Aim 1: Identify DNAm and RNAexp differences in NAc and DLPFC of AUD cases vs. controls. Aim 2: Map QTLs that underlie AUD-related DNAm and RNAexp differences in NAc and DLPFC. Aim 3: Test association of eQTLs and meQTLs with AUD risk. Aim 4: Functionally characterize alcohol consumption and AUD GWAS loci. Aims 1, 2, and 4 will leverage multiple `omics data from postmortem human brain tissues from AUD case and control decedents (total N = 220, the largest-to-date postmortem brain collection with AUD status known). Aim 3 will use existing GWAS samples with AUD defined by DSM-5 (the most up-to-date version of the Diagnostic and Statistical Manual of Mental Disorders): total N = 76,296. Aim 4 will cycle back to the approaches taken in preceding aims, but it will focus on the 80+ prior GWAS-identified loci. Our integration of epigenomics, transcriptomics, and genomics in human brain and extension into GWAS meta-analysis of AUD will greatly improve the likelihood of meaningful discovery by targeting gene regions and specific variants with high biological relevance, specifically in the brain, while retaining a genome-wide scope.


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 = -$63,504 )
2026	2023	RESEARCH TRIANGLE INSTITUTE	3040 CORNWALLIS RD	DURHAM	NC	27709	DURHAM	USA	Alcohol Research Programs	000	5	1/14/2026	NON-COMPETING CONTINUATION	-$63,504
														Subtotal = -$63,504

Issue Date FY: 2023 ( Subtotal = $571,873 )
2023	2023	RESEARCH TRIANGLE INSTITUTE	3040 E CORNWALLIS RD	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Alcohol Research Programs	000	5	8/1/2023	NON-COMPETING CONTINUATION	$571,873
														Subtotal = $571,873

Issue Date FY: 2022 ( Subtotal = $572,697 )
2022	2022	RESEARCH TRIANGLE INSTITUTE	3040 E CORNWALLIS RD	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Alcohol Research Programs	000	4	8/7/2022	NON-COMPETING CONTINUATION	$572,697
														Subtotal = $572,697

Issue Date FY: 2021 ( Subtotal = $605,741 )
2021	2021	RESEARCH TRIANGLE INSTITUTE	3040 E CORNWALLIS RD	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Alcohol Research Programs	000	3	8/3/2021	NON-COMPETING CONTINUATION	$605,741
														Subtotal = $605,741

Issue Date FY: 2020 ( Subtotal = $614,693 )
2020	2020	RESEARCH TRIANGLE INSTITUTE	3040 E CORNWALLIS RD	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Alcohol Research Programs	000	2	8/10/2020	NON-COMPETING CONTINUATION	$614,693
														Subtotal = $614,693

Issue Date FY: 2019 ( Subtotal = $625,964 )
2019	2019	RESEARCH TRIANGLE INSTITUTE	3040 E CORNWALLIS RD	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Alcohol Research Programs	000	1	9/24/2019	NEW	$625,964
														Subtotal = $625,964

Grand Total All Awards = $2,927,464

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Multi 'Omics Integration and Neurobiological Signatures of Alcohol Use Disorder

Award Number: R01AA027049

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/24/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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