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.