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Dissecting the Impact of Localized Ancestry on Gene Expression Regulation to Elucidate Mechanisms of Genetic Risk

Award Number: R01HL151152
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Dissecting the Impact of Localized Ancestry on Gene Expression Regulation to Elucidate Mechanisms of Genetic Risk - Cardiometabolic diseases (CMD) and their risk factors are leading causes of morbidity and mortality and are increasing in frequency. Despite this increase, there are major gaps in understanding fundamental mechanisms that lead to, and are perturbed by, CMD. For example, limited inclusion of admixed populations restricts opportunities to incorporate differences in ancestry across chromosomes (i.e., local ancestry) to link genetic variants with CMD. Further, CMD polygenic risk scores (PRS) are systematically less accurate in admixed populations compared with predominantly European ancestry (EA) populations, which may in part reflect pervasive local ancestry effects that introduce heterogeneity in variant effect size and direction. These evidence gaps limit the promises of precision medicine for everyone. Our preliminary data in two distinct admixed groups show that more than 50% of genes with expression quantitative trait loci (eQTLs) have one or more eQTL with significantly different effects depending on the local ancestry at the site of the gene. Understanding and leveraging this heterogeneity may be paradigm shifting for genomic studies in admixed populations. Indeed, we find that colocalizing these local ancestry-based (LAB) eQTLs with genome wide association study (GWAS) data enriches identification of genes with functional effects on CMD and that differences in performance of CMD polygenic risk scores (PRS) for admixed populations compared with EA populations, may in part reflect universal local ancestry effects that introduce heterogeneity in variant effect size and direction across populations. To improve CMD mechanistic understanding and clinical characterization of risk, expanded studies are needed to characterize and utilize LAB QTLs across additional omics and populations. In this renewal, we, the Population Architecture using Genomics and Epidemiology (PAGE) study investigators, continue our 15-year history of collaborative CMD omics research across populations by improving the genomics translational pipeline. Leveraging our cutting-edge statistical methods and decades-long experience with complex data (>600,000 admixed individuals) with rich phenotypic and omics characterization, we propose a suite of local ancestry-aware approaches to improve biological understanding of CMD genetics and identify actionable targets. Our aims will: (1) assess the impact of local ancestry on regulation of transcriptomic and proteomic factors in CMD-relevant tissues; (2) identify transcriptomics and proteins that affect or are affected by CMD, including differentially by underlying ancestry; and (3) characterize the phenotypic landscape affected by LAB QTL-informed CMD PRS across populations. Our data suggests that failure to account for local ancestry in omics analyses substantially reduces power in admixed populations. Via these aims we will pioneer an ancestry-aware methodological framework that improves understanding of CMD and the broader medical phenome, while increasing precision in genomic medicine.


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 = $2,283,828 )
2026	2026	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	6	7/22/2026	COMPETING CONTINUATION	$2,283,828
														Subtotal = $2,283,828

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	5	9/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	5	8/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $2,460,691 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	5	8/16/2023	NON-COMPETING CONTINUATION	$2,460,691
														Subtotal = $2,460,691

Issue Date FY: 2022 ( Subtotal = $2,553,156 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	005	4	7/28/2022	NON-COMPETING CONTINUATION	$2,466,052
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	006	4	8/3/2022	NON-COMPETING CONTINUATION	$0
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	008	4	8/18/2022	SUPPLEMENT FOR EXPANSION	$132,000
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	012	3	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,423,047
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	007	3	8/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	002	3	6/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,343,193
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	003	2	6/30/2022	NON-COMPETING CONTINUATION	$0
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	2	5/9/2022	SUPPLEMENT FOR EXPANSION	-$44,896
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	011	2	8/31/2022	SUPPLEMENT FOR EXPANSION	-$83,770
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	004	3	7/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	001	2	6/21/2022	NON-COMPETING CONTINUATION	-$1,343,193
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	010	2	8/31/2022	NON-COMPETING CONTINUATION	-$1,161,337
2022	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	009	1	8/31/2022	NEW	-$177,940
														Subtotal = $2,553,156

Issue Date FY: 2021 ( Subtotal = $2,633,196 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	2	7/17/2021	NON-COMPETING CONTINUATION	$2,504,530
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	001	2	7/29/2021	SUPPLEMENT FOR EXPANSION	$128,666
														Subtotal = $2,633,196

Issue Date FY: 2020 ( Subtotal = $2,404,260 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cardiovascular Diseases Research	000	1	8/20/2020	NEW	$2,404,260
														Subtotal = $2,404,260

Grand Total All Awards = $12,335,131

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Dissecting the Impact of Localized Ancestry on Gene Expression Regulation to Elucidate Mechanisms of Genetic Risk

Award Number: R01HL151152

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/20/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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