Air pollution and Dementia: Exploring genetic, cardiovascular, and epigenetic moderators and mechanisms

背景：痴呆症是一个主要的，不断增长的公共卫生优先事项。一个人的基因组成会使他们患痴呆症的风险更高，但也有重要的环境预测因素会增加风险。空气污染就是其中之一，全世界都有证据表明污染对大脑健康的负面影响。这些人口研究非常庞大，对数百万人进行了抽样调查，但他们忽略了一个人的遗传倾向。污染物可能与一个人患痴呆症的遗传风险相互作用：更大的空气污染可能会增加一个人的遗传风险，而一个人的遗传构成可能意味着对环境损害的更大易感性或弹性。空气污染还可以预测心血管疾病（CVD），这反过来又可以预测痴呆症，并且CVD本身和/或CVD风险因素可能会介导污染物与痴呆症之间的相关性。空气污染也可能通过改变生物机制影响大脑健康，例如加速端粒（保护染色体末端的核苷酸）缩短和改变DNA甲基化（可以改变基因表达），两者都与衰老密切相关。 目的：该项目的总体目标是研究整个生命周期的空气污染暴露与痴呆症/认知能力下降风险之间的关联。目的包括：1）量化基因与环境（空气污染）相互作用对痴呆症的影响。这将通过以下方式完成：a）将经典双胞胎设计应用于来自瑞典双胞胎登记处（STR）的数据，模拟基因与环境的相互作用，以研究痴呆症的遗传和环境差异是否因暴露于空气污染的水平而不同，以及B）在洛锡安出生队列（LBC）、英国生物库和STR中模拟痴呆症与空气污染相互作用的多基因风险评分，专门模拟空气污染和痴呆症遗传风险之间的相互作用对痴呆症状态（英国生物银行，STR）和认知能力下降（LBC，其中痴呆症分析将不太强大）。 2)测试空气污染物是否与痴呆症有因果关系这将在STR中使用不一致MZ共双胞胎对照设计进行检验（N= 1，214对）。在这个设计中，MZ双胞胎的基因和早期环境完全匹配，可以比较他们成年后的环境暴露与痴呆状态。一个因果模型将得到支持，如果双胞胎与更大的污染暴露是痴呆症的情况下。 3)测试CVD是否介导空气污染物对痴呆症的影响。这将通过将CVD诊断纳入LBC和STR中空气污染和痴呆症的调解模型中进行检查，同时考虑CVD和痴呆症的遗传风险。 4)测试增加的空气污染物暴露（在LBC和STR中的寿命）是否与较短的端粒长度和整个基因组的甲基化探针有关，如果是这样，这些是否介导了空气污染物暴露和痴呆症之间的关系。独特的是，甲基化数据是纵向的（长达20年），因此我们也可以将它们与空气污染的纵向测量联系起来。

Background: Dementia is a major, growing public health priority. A person's genetic makeup can place them at higher risk of dementia, but there are also important environmental predictors that can increase risk. Air pollution is one of these, with evidence converging worldwide on the negative effects of pollution on brain health. These population studies have been extremely large, sampling millions of people, but they ignore a person's genetic predisposition. It is possible that pollutants interact with a person's genetic risk of dementia: greater air pollution might increase one's genetic risk, and one's genetic makeup can imply greater susceptibility or resilience to environmental insults. Air pollution also predicts cardiovascular disease (CVD), which in turn predicts dementia, and it is plausible that CVD itself and/or CVD risk factors mediate the observed association between pollutants and dementia, as indicated in prior work. It is also possible that air pollution affects brain health through altering of biological mechanisms such as accelerated telomere (nucleotides that protect the end of chromosomes) shortening and altered DNA methylation (which can change gene expression), both of which are strongly associated with ageing. Aims: The overarching aim of the project is to study the association between air pollution exposure across the lifespan and risk of dementia/cognitive decline. The aims include : 1) quantify the effects of gene by environment (air pollution) interaction on dementia. This will be done by a) applying classical twin design to data from the Swedish Twin Registry (STR), modelling gene by environment interactions to study whether genetic and environmental variance in dementia differ by levels of exposure to air pollution, and b) modelling a polygenic risk score for dementia in interaction with air pollution in the Lothian Birth Cohorts (LBCs), UK Biobank and STR, to specifically model interaction between air pollution and genetic risk of dementia on dementia status (UK Biobank, STR) and cognitive decline (LBCs where dementia analysis will be less powerful). 2) test whether air pollutants are causally related to dementia. This will be tested using a discordant MZ co-twin control design in the STR (N=1,214 pairs). In this design, MZ twins are perfectly matched for their genes and early environments, enabling comparison of their environmental exposure in adulthood in relation to their dementia status. A causal model would be supported if the twin with greater pollution exposure is the dementia case. 3) test if CVD mediates the effect of air pollutants on dementia. This will be examined by incorporating diagnoses of CVD in mediation models of air pollution and dementia in the LBCs and the STR while accounting for genetic risk of CVD and dementia. 4) test whether increased air pollutant exposure (over the lifetime in the LBCs and in the STR) is related to shorter telomere length and to methylation probes across the genome, and if so, whether these mediate the relationship between the air pollutant exposure and dementia. Uniquely, methylation data are available longitudinally (up to 20 years), so that we can also link them with longitudinal measures of air pollution.