The power of the environment: Environmental mediation of genetic liability

儿童肥胖的后果仍然是英国最大的公共健康负担之一。三分之一的儿童在10岁时已经超重或肥胖。这个问题尤其严重，因为肥胖与许多健康状况有关，比如糖尿病、癌症和抑郁症。现在有大量证据表明，肥胖会在家族中遗传，但单靠基因并不能解释目前人口中肥胖人数的上升。因此，环境因素被认为是导致这种发展的原因。正是这种双重决定仍然是矛盾的——肥胖怎么可能同时由基因和环境来解释？这种复杂性对公共卫生干预意味着什么？本奖学金拟进行的研究将调查这些问题。我的目标是汇集两个领域的方法论工具：多基因评分和中介分析。多基因得分是个体水平的得分，它总结了某种疾病或特征的遗传倾向性。中介分析首先确定风险因素与后来的健康结果之间的关联，然后旨在确定这种关联在多大程度上可以用第三个变量（中介）来解释。在儿童肥胖的背景下，我们已经知道遗传和环境因素很重要。然而，目前尚不清楚环境因素如何保护遗传责任。在这项研究中，我的目的是了解环境因素如何介导或调节遗传倾向性（由多基因评分表示）对BMI的影响。我的主要问题是：1。父母的喂养方法，如提供食物来缓解、增强或缓冲遗传倾向与儿童后期体型之间的联系吗？如果我们改变父母的喂养策略，可以实现什么？儿童的体育活动是否在儿童遗传倾向和后来的体型之间起中介作用？如果体育活动水平增加会发生什么？即使遗传风险没有遗传，母亲的遗传风险是否会影响孩子的体型？遗传责任与家庭住宅的建筑环境（如绿色空间和公共交通）之间有什么联系？为了解决这些问题，我将组合数据集，这些数据集已经包含了我需要的所有信息。这使得本研究非常高效和实用。由于其新颖性，我计划比较两种不同的方法来研究中介——一种是传统的更非正式的结构方程建模方法，另一种是最近发展起来的正式反事实方法。比较这些不同的方法将非常有用，因为它可以增强我们对结果的信心，也可以帮助其他研究人员研究同样复杂但普遍存在的问题。这些问题对公共卫生非常重要。多基因评分很容易通过商业供应商获得，但最近也被提议纳入NHS标准实践。然而，目前尚不清楚多基因评分与环境干预之间的关系，以及这些干预是否能缓解肥胖的遗传风险。儿童肥胖的后果一直是最大的健康挑战之一，它可能影响到整个家庭。这项研究有可能揭示儿童肥胖的一些潜在机制，并强调环境因素可以起到保护作用的途径。

The consequences of childhood obesity remain one of the biggest public health burdens in the UK. 1 in 3 children are already overweight or obese by age 10 years. This is especially problematic because obesity has been linked to many health conditions, such as diabetes, cancer and depression. There is now substantive evidence that obesity runs in families, but genetics alone cannot explain the current rise of obesity in the population. So environmental factors have been proposed to be causal for this development. It is this dual determination, that remains paradoxical - how is it possible that obesity is explained by both genes and environments at the same time and what does this complexity mean for public health interventions? The proposed research for this fellowship will investigate these issues. My aim is to bring together methodological tools from two fields: polygenic scores and mediation analyses. Polygenic scores are individual level scores that summarise the genetic liability for an illness or characteristic. Mediation analysis first establishes the association between a risk factor and a later health outcome, and then aims to establish how much of this association can be explained by a third variable (the mediator). In the context of childhood obesity, we already know that genetic and environmental factors are important. However, it is not known how environmental factors might be protective of genetic liability. In this fellowship, my aim is to understand how environmental factors can mediate or moderate the effect of genetic liability (indicated by a polygenic score) for BMI. My main questions are: 1. Do parental feeding practices, such as offering food to soothe, enhance or buffer the association between genetic liability and later childhood body size, and what could be achieved if we changed parental feeding strategies?2. Does the child's physical activity mediate the association between childhood genetic liability and later body size, and what would happen if levels of physical activity increased?3. Can maternal genetic risk influence the child's body size, even though the genetic liability are not passed on?4. What is the association between genetic liability and the built environment of the family home, such as access to green spaces and public transport? In order to address these questions, I will combine data sets, which already have all the information that I need. This makes this research very efficient and pragmatic. Due to the novelty, I am planning to compare two different methods to investigate mediation - one is the traditional more informal approach of structural equation modelling and the other is a more recently developed formal counterfactual approach. Comparing these different methods will be very useful because it can strengthen our confidence in the results, but also can help other researchers studying similarly complicated but ubiquitous questions. These questions are of great importance to public health. Polygenic scores are readily available through commercial providers, but also have recently been proposed to be included into NHS standard practice. However, it is unknown how polygenic scores relate to environmental interventions and if these interventions can buffer genetic liability for obesity. Consequences of childhood obesity persists as one of the biggest health challenges, which can affect the entire family. This research has the potential to uncover some of the mechanisms underlying childhood obesity and highlight the pathways by which environmental factors can be protective.