R01HG011646

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 populations 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.

University Of Southern California

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Los Angeles, California 90033 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 287% from $836,184 to $3,238,939.