Using genetics to understand how modifiable lifestyle changes may prevent disease in later life: A life course approach

了解儿童和青少年时期可改变的因素（包括生活方式）影响我们疾病风险的方式具有挑战性。例如，早年肥胖的人患心血管疾病的风险会增加。然而，由于这些人倾向于在以后的生活中保持肥胖，目前还不清楚通过改变生活方式可以逆转多少这种风险。此外，复杂疾病通常由多个风险因素决定，这些风险因素可能独立于一个或另一个，也可能不独立于另一个。这个博士将使用大型数据集来开发一个假定的因果图，说明多种生活方式因素如何影响疾病风险。将强调生命早期的风险，因为结果表明，童年时期的风险可以逆转，这将产生一个重要的可翻译的信息，可以影响社会政策。相反，必须更好地了解哪些早期生命风险因素对疾病易感性具有不可改变的影响，而这种影响无法通过改变生活方式来减轻。将应用流行病学中称为孟德尔随机化（MR）的技术原理。这种方法利用遗传学来解开因果关系，考虑到我们的基因在出生时是随机遗传的，这一点特别强大。因此，它们对干扰和反向因果关系等因素具有鲁棒性，这些因素阻碍了观察分析。

Understanding the manner in which modifiable factors (including lifestyle) during childhood and adolescence influence our risk of disease is challenging. For instance, individuals who are obese in early life have elevated risk of cardiovascular disease. However, as these individuals tend to remain obese into later life, it is unclear how much of this conferred risk can be reversed by making lifestyle changes. Furthermore, complex disease is typically determined by multiple risk factors, which may or may not act independently of one and other. This PhD will use large datasets to develop a putative causal map of how multiple lifestyle factors influence disease risk. There will be an emphasis on early life exposures, as results suggesting that conferred risk during childhood can be reversed will have an important translatable message that can impact social policy. Conversely, it is imperative to better understand which early life risk factors have an immutable influence on disease susceptibility which cannot be mitigated through lifestyle modifications. The principles of a technique in epidemiology known as Mendelian randomization (MR) will be applied. This approach uses genetics to disentangle causal relationships, which is particularly powerful given that our genes are inherited randomly at birth. As such they are robust to factors such as confounding and reverse causation which hinder observational analyses.