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Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians

Award Number: R01HG011646
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians - Project Summary / Abstract Native Hawaiians are one of the most understudied, ethnic minority population in the United States. Compared to their European or Asian American counterparts, Native Hawaiians exhibit alarming rates of obesity, diabetes, and other related chronic health conditions, even after adjusting for common modifiable risk factors. Yet few genetic research has focused on Native Hawaiians. Genomic resources such as imputation reference panels are also generally lacking for Native Hawaiians, preventing comprehensive genetic investigations to be undertaken with this population. Therefore, compared to other continental populations, Native Hawaiians are not on pace to reap the benefits we have gained from large scale genomic studies of diseases. While there are growing recognitions of the need to include more non-European individuals in genomic studies, an often-ignored fact is that the disease risks for members of a population are intimately tied to the evolutionary history of that population. Theoretical and empirical studies have shown that the demographic history of a population will impact the genotype-phenotype relationship in ways specific to that population. Therefore, a better incorporation of evolutionary thinking will help better understand the genetic basis for differences in disease risk among diverse populations today. To this end, we are proposing to develop an integrative framework that combines principles of both population genetics and genetic epidemiology to understand why Native Hawaiians show excess risk in obesity and type-2 diabetes (T2D). Specifically, by leveraging newly generated whole genome sequences (WGS) and existing array genotype data on >5,600 Native Hawaiians, we will first characterize the demographic history of the Native Hawaiians and the impact of this history to the enrichment of functional alleles. These alleles are likely under natural selection, important for the health of Native Hawaiians, but would be easily missed if one only studies other continental populations that exist in large number. Secondly, by combining with existing WGS from Samoans, we will construct the first Polynesian-specific imputation reference panel. We will then impute and conduct the largest association study to date in >10,000 Polynesian individuals and >2,000 Micronesian individuals for obesity and T2D. Thirdly, we will evaluate the transferability of risk stratification models for obesity and T2D based on polygenic risk scores (PRS) in Native Hawaiians, determine the population genetic and non-genetic factors that may have contributed to the expected poor transferability of these models, and assess if Polynesian-specific summary statistics will improve the risk stratification models. Finally, we will conduct pilot studies in the form of focus groups to understand the concerns Native Hawaiian community may have in future participation of genomic research. The results from this proposal will help motivate and guide the design of future genomic studies in this understudied population, identify population-specific alleles influencing obesity and T2D, and improve future risk stratification models of diseases in Native Hawaiians and other Polynesian populations.


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 = $751,774 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Human Genome Research	000	5	8/3/2026	NON-COMPETING CONTINUATION	$751,774
														Subtotal = $751,774

Issue Date FY: 2025 ( Subtotal = $804,459 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Human Genome Research	000	4	9/16/2025	NON-COMPETING CONTINUATION	$804,459
														Subtotal = $804,459

Issue Date FY: 2024 ( Subtotal = $812,012 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Human Genome Research	000	3	7/29/2024	NON-COMPETING CONTINUATION	$812,012
														Subtotal = $812,012

Issue Date FY: 2023 ( Subtotal = $786,284 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Human Genome Research	001	2	8/14/2023	NON-COMPETING CONTINUATION	$786,284
2023	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Human Genome Research	000	1	6/2/2023	NEW	$0
														Subtotal = $786,284

Issue Date FY: 2022 ( Subtotal = $836,184 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Human Genome Research	000	1	8/23/2022	NEW	$836,184
														Subtotal = $836,184

Grand Total All Awards = $3,990,713

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Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians

Award Number: R01HG011646

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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