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

项目摘要/摘要 夏威夷原住民是美国最未被研究的少数民族人口之一。相比较 与欧洲或亚裔美国人相比，夏威夷原住民的肥胖率、糖尿病、 以及其他相关的慢性健康状况，即使在对常见的可改变的风险因素进行调整之后也是如此。然而，几乎没有人 基因研究的重点是夏威夷原住民。基因组资源，如归因参考板 对于夏威夷原住民来说也普遍缺乏，阻止了全面的基因研究 在这群人中进行的。因此，与其他大陆人口相比，夏威夷原住民并不是 我们正在从大规模的疾病基因组研究中获得好处。 虽然越来越多的人认识到有必要在基因组中包括更多的非欧洲人 研究发现，一个经常被忽视的事实是，人群成员的疾病风险与 该种群的进化史。理论和经验研究表明，人口统计 一个群体的历史将以该群体特有的方式影响基因-表型关系。 因此，更好地融入进化思维将有助于更好地理解 今天，不同人群之间的疾病风险差异。为此，我们建议制定一项 结合了群体遗传学和遗传流行病学原理的综合框架 了解为什么夏威夷原住民在肥胖和2型糖尿病(T2D)方面表现出过高的风险。具体地说，通过 利用新生成的全基因组序列(WGS)和5,600上现有的阵列基因数据 夏威夷原住民，我们将首先描述夏威夷原住民的人口学历史以及 这一历史赋予了功能等位基因的丰富性。这些等位基因很可能是自然选择下的，对 土著夏威夷人的健康，但如果只研究其他大陆人口，很容易被忽视 大量存在。其次，通过与萨摩亚现有的WGS相结合，我们将建造第一个 波利尼西亚特定的归责参考小组。然后，我们将委托并进行最大规模的关联研究 到目前为止，有10,000名波利尼西亚人和2,000名密克罗尼西亚人患有肥胖症和T2D。第三，我们 将评估基于多基因风险评分的肥胖和T2D风险分层模型的可转移性 (PR)在夏威夷原住民中，确定可能对人口遗传和非遗传因素有贡献的人群 这些模型的预期较差的可转移性，并评估波利尼西亚特定的摘要统计是否将 完善风险分层模型。最后，我们将以专题小组的形式进行试点研究，以 了解夏威夷原住民社区在未来参与基因组研究时可能会关注的问题。这个 这一建议的结果将有助于激励和指导未来基因组研究的设计 人群，识别影响肥胖和T2D的人群特定等位基因，并改善未来的风险分层 夏威夷原住民和其他波利尼西亚人的疾病模型。

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.