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A Framework for Translating Polygenic Findings Related to Alcohol Use Disorder Across Species

Award Number: R01AA029688
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: 09/16/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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A Framework for Translating Polygenic Findings Related to Alcohol Use Disorder Across Species - Summary Alcohol use disorder (AUD) causes 1 in 20 deaths worldwide and imposes huge economic costs on society. Twin studies have shown that the risk for developing AUD is heritable. Genome wide association studies (GWAS) have indicated that, like most psychiatry diseases, AUD is highly polygenic. Although GWAS in both humans and rodents are powerful techniques, with different strengths and weaknesses, techniques to integrate the two are poorly developed. GWAS identify individual SNPs that influence a trait; because those SNPs are species specific, polygenic risk scores (PRS) and similar approaches cannot be used to transfer information across species. To address this limitation, we are proposing a framework for transferring polygenic signals across species. We introduce the concept of polygenic transcriptomic risk scores (PTRS). Whereas PRS sum the effects of many SNPs, a PTRS sums the effects of genetically predicted transcript abundance across many genes. Because these effects are at the gene, rather than SNP level, they can be applied to orthologous genes in other species. The extent to which a PTRS for AUD that was developed in humans might predict rodent behaviors believed to be relevant to AUD is currently unknown. In this grant we will assess whether PTRS can be used to translate polygenic signals related to AUD between humans and rodents. We focus on AUD because of the existence of high quality human GWAS data about AUD and related traits like alcohol consumption. In Aim 1, we will phenotype 1,250 HS rats for multiple alcohol self-administration traits. In Aim 2, we will perform GWAS and transcriptome wide association analysis (TWAS) for alcohol-related traits in the rats from Aim 1. In Aim 3, we will build PTRS for AUD and related traits and optimize them for portability across species. These aims address a critical limitation, namely the inability to transfer polygenic knowledge between species, which is inhibiting progress towards a deeper understanding of how polygenic liability for AUD alters molecular and cellular processes, brain circuits and behaviors. If successful, our results will open new avenues for research aimed at prediction, prevention, and treatment of AUD.


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 = $519,442 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	8/20/2026	NON-COMPETING CONTINUATION	$519,442
														Subtotal = $519,442

Issue Date FY: 2025 ( Subtotal = $519,319 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	4	8/18/2025	NON-COMPETING CONTINUATION	$519,319
														Subtotal = $519,319

Issue Date FY: 2024 ( Subtotal = $959,758 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	7/10/2024	SUPPLEMENT FOR EXPANSION	$382,829
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	3	8/6/2024	NON-COMPETING CONTINUATION	$576,929
														Subtotal = $959,758

Issue Date FY: 2023 ( Subtotal = $551,837 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	8/18/2023	NON-COMPETING CONTINUATION	$551,837
														Subtotal = $551,837

Issue Date FY: 2022 ( Subtotal = $569,519 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	9/16/2022	NEW	$569,519
														Subtotal = $569,519

Grand Total All Awards = $3,119,875

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A Framework for Translating Polygenic Findings Related to Alcohol Use Disorder Across Species

Award Number: R01AA029688

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: 09/16/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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