Clarifying risk and protective factors for dementia with the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium

总结/摘要 本申请是对PAR-17-054的响应，该申请要求合并多个现有队列，以便 提高统计能力，明确阿尔茨海默病和相关痴呆风险和保护因素 (AD/ADRD）。虽然公认ADRD的发生反映了多个基因的影响， 多种环境和生活方式风险和保护因素，旨在阐明潜在的信息 基因与环境的相互作用已经很少了。因此，我们建议雇用一个大型财团， 成人发育和衰老的纵向双胞胎研究，测量风险和保护因素， 不同的生命阶段，以解决有关ADRD病因机制的关键问题。通过有效治疗 双胞胎中的一个作为另一个的对照，我们将测试与生活方式，健康， 心理社会因素，同时控制遗传因素，从而加强因果关系的推断， 观察性研究我们还将使用双胞胎设计来测试风险和风险之间的关联程度。 保护因子和ADRD反映了共同的遗传或共同的环境解释。除了 在配对内和定量双胞胎模型中，我们将使用多基因风险评分（PRS）作为个体 ADRD的遗传风险，以测试ADRD的遗传风险是否会改变对其他风险的易感性， 因素，以及特定风险和保护因素的PRS，以测试这些因素的遗传风险是否会改变其 与ADRD的关系我们特别注重澄清教育与发展之间关系的性质， ADRD;中年肥胖、血管风险、抑郁和体力活动;以及 遗传风险、暴露于特定风险因素、对特定风险因素的易感性以及 与特定风险因素的遗传相互作用。这些问题为干预措施的设计提供了重要信息， 预防或减缓痴呆症的发生。基因与环境相互作用联盟 多项研究（IGEMS）包括美国的八项双胞胎登记研究，瑞典、丹麦、芬兰和澳大利亚。 IGEMS带来了近50，000对单独的双胞胎，其中有超过5000对同卵双胞胎对进行对内差异 近7000对同性异卵双胞胎和3000多对异性双胞胎 模型结果包括：临床诊断的痴呆症;痴呆症诊断通过与国家 健康登记;心理测量学确定的MCI;基于认知功能的潜在痴呆指标评分 功能评价。IGEMS参与者的一个大子集具有全基因组基因分型， 计算PRS。对于风险和保护因素、介质和协变量的分析，我们有数据 从中年和中年以后收集的调查以及从与行政数据的联系中，征兵 记录和健康登记。已经统一的措施包括：教育、职业、认知测试， 体重指数，抑郁，焦虑。

SUMMARY/ABSTRACT This application is in response to PAR-17-054, which calls for combining multiple existing cohorts in order to improve statistical power and clarify risk and protective factors for Alzheimer’s disease and related dementias (AD/ADRD). While it is well-recognized that ADRD occurrence reflects the influences of multiple genes and multiple environmental and lifestyle risk and protective factors, designs to elucidate potentially informative gene-environment interplay have been rarer. Consequently we propose to employ a large consortium of longitudinal twin studies of adult development and aging, with measures of risk and protective factors across different life stages, to address key questions about etiological mechanisms in ADRD. By effectively treating one twin as the control for the other, we will test for risk or protection associated with lifestyle, health, and psychosocial factors while controlling for genetic factors, thereby strengthening causal inferences from observational studies. We will also use twin designs to test the extent to which the association between risk or protective factor and ADRD reflects shared genetic or shared environmental explanations. In addition to within-pair and quantitative twin models, we will use polygenic risk scores (PRS) as indicators of individual genetic risk for ADRD to test whether genetic risk for ADRD alters susceptibility to other risk and protective factors, and PRS for specific risk and protective factors to test whether genetic risk for these factors alter their association with ADRD. We especially focus on clarifying the nature of the relationship between education and ADRD; midlife obesity, vascular risk, depression, and physical activity; and sex or gender differences in genetic risk, exposure to specific risk factors, susceptibility to specific risk factors, and sex differences in genetic interactions with specific risk factors. These questions importantly inform the design of interventions to prevent or slow occurrence of dementia. The consortium on Interplay of Genes and Environments across Multiple Studies (IGEMS) includes eight twin registries in the U.S., Sweden, Denmark, Finland, and Australia. IGEMS brings nearly 50,000 individual twins, with over 5000 identical twin pairs for within-pair difference models, nearly 7000 same-sex fraternal twin pairs, and over 3000 opposite sex pairs for sex difference models. Outcomes include: clinically diagnosed dementia; dementia diagnoses obtained by linkage to national health registries; psychometrically determined MCI; scores on a latent dementia indicator based on cognitive and functional evaluations. A large subset of IGEMS participants has genome wide genotyping from which we have computed PRS. For analyses of risk and protective factors, mediators, and covariates, we have data from surveys collected in midlife as well as later and from linkages to administrative data, e.g., conscription records and health registries. Already harmonized measures include: education, occupation, cognitive tests, BMI, depression, anxiety.