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.

项目概要/摘要 夏威夷原住民是美国最受关注的少数族裔之一。比较的 与欧洲或亚裔美国人相比，夏威夷原住民的肥胖、糖尿病、 和其他相关的慢性健康状况，即使在调整常见的可改变风险因素后也是如此。然而很少 遗传学研究主要集中在夏威夷原住民身上。基因组资源，例如插补参考面板 夏威夷原住民也普遍缺乏这些基因，从而阻碍了全面的基因调查 与这一人群进行的。因此，与其他大陆人口相比，夏威夷原住民并不 我们正在努力从大规模疾病基因组研究中获益。 尽管人们越来越认识到需要将更多非欧洲个体纳入基因组研究中 研究中，一个经常被忽视的事实是，人群的疾病风险与 该种群的进化历史。理论和实证研究表明，人口 一个群体的历史将以该群体特有的方式影响基因型-表型关系。 因此，更好地结合进化思想将有助于更好地理解基因的遗传基础。 当今不同人群之间疾病风险的差异。为此，我们建议开发一个 结合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患肥胖症和 2 型糖尿病 (T2D) 的风险过高。具体来说，通过 利用新生成的全基因组序列 (WGS) 和现有阵列基因型数据超过 5,600 个 夏威夷原住民，我们将首先描述夏威夷原住民的人口历史及其影响 这段历史丰富了功能等位基因。这些等位基因可能是在自然选择下，对于 夏威夷原住民的健康状况，但如果只研究其他大陆人口，很容易被忽视 大量存在。其次，结合萨摩亚现有的WGS，我们将构建第一个 波利尼西亚特定插补参考面板。然后我们将进行最大规模的关联研究 迄今为止，已有超过 10,000 名波利尼西亚人和超过 2,000 名密克罗尼西亚人患有肥胖症和 T2D。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，确定可能造成影响的群体遗传和非遗传因素 预期这些模型的可移植性较差，并评估波利尼西亚特定的汇总统计数据是否会 完善风险分层模型。最后，我们将以焦点小组的形式进行试点研究 了解夏威夷原住民社区对未来参与基因组研究可能存在的担忧。这 该提案的结果将有助于激励和指导该领域未来基因组研究的设计 人群，确定影响肥胖和 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的疾病模型。