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

利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型

• 批准号: 10365815
• 负责人: Charleston Chiang
• 金额: $ 83.62万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365815
• 关键词: Address; Age; Alleles; Asian Americans; Body mass index; Catalogs; Censuses; Chronic; Communities; Complex; Data; Demographic Impact; Diabetes Mellitus; Diet; Disease; Disease model; East Asian; Ethnic group; European; Exhibits; Focus Groups; Future; Genes; Genetic; Genetic Research; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Grant; Habitats; Health; High Prevalence; Human; Individual; Investigation; Linkage Disequilibrium; Masks; Meta-Analysis; Metabolic Diseases; Minority Groups; Modeling; Native Hawaiian; Native Hawaiian or Other Pacific Islander; Natural Selections; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oceania; Pattern; Phenotype; Philippines; Pilot Projects; Play; Polynesian; Population; Population Genetics; Population Heterogeneity; Population Sizes; Race; Recording of previous events; Research; Resources; Risk; Risk Factors; Role; Samoan; Shapes; Socioeconomic Status; Thinking; Underserved Population; United States; Variant; base; biobank; clinical practice; design; disorder risk; efficacy evaluation; ethnic minority population; experience; genetic architecture; genetic epidemiology; genetic risk factor; genome sequencing; genome wide association study; genome-wide; health disparity; high risk; improved; insight; member; modifiable risk; non-genetic; novel; obese person; obesity risk; pathogen; polygenic risk score; prevent; programs; prospective; recruit; risk stratification; risk variant; sex; statistics; success; trait; whole genome

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.

项目摘要 /摘要 夏威夷原住民是美国最流行，少数民族的人口之一。比较的 对于他们的欧洲或亚裔美国人来说，夏威夷原住民表现出令人震惊的肥胖症，糖尿病， 以及其他相关的慢性健康状况，即使在调整了常见的可修改风险因素之后。但是很少 遗传学研究集中在夏威夷人。基因组资源，例如归纳参考面板 夏威夷原住民通常也缺乏，阻止了全面的遗传研究 在这个人群中进行。因此，与其他大陆人口相比，夏威夷原住民不是 以大规模的疾病基因组研究获得的好处，我们从中获得了收益。 虽然人们越来越认识到需要在基因组中包括更多的非欧洲个体 研究，一个经常命名的事实是，人口成员的疾病风险与 该人群的进化史。理论和实证研究表明人口 人口的历史将以特定于该人群的方式影响基因型 - 表型关系。 因此，更好地纳入进化思维将有助于更好地了解 当今不同人群中疾病风险的差异。为此，我们建议开发 将种群遗传学和遗传流行病学的原理结合到的综合框架与 理解为什么夏威夷人在肥胖和2型糖尿病（T2D）中表现出多余的风险。具体来说，由 利用新生成的整个基因组序列（WGS）和现有阵列基因型数据> 5,600 夏威夷原住民，我们将首先描述夏威夷原住民的人口历史和 这一历史富集功能等位基因。这些等位基因可能是自然选择的，对于 夏威夷原住民的健康，但如果只学习其他大陆种群，很容易错过 大量存在。其次，通过与萨摩亚人的现有WG结合，我们将构建第一个 波利尼西亚特定的插补参考面板。然后，我们将重算并进行最大的协会研究 迄今为止，有10,000个波利尼西亚人和> 2,000个肥胖症和T2D的Microneian个人。第三，我们 将根据多基因风险评分评估肥胖和T2D风险分层模型的可转移性 （PRS）在夏威夷原住民中，确定可能造成的种群遗传和非遗传因素 这些模型的预期可传递性不佳，并评估波利尼西亚特定的摘要统计数据是否会 改善风险分层模型。最后，我们将以焦点小组的形式进行试验研究 了解夏威夷当地社区可能对基因组研究的未来参与的担忧。这 该建议的结果将有助于激励和指导该研究的未来基因组研究的设计 人口，识别影响肥胖症和T2D的人群特异性等位基因，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群中的疾病模型。