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

理解童年和青春期的可改变因素(包括生活方式)如何影响我们的疾病风险是具有挑战性的。例如，早年肥胖的人患心血管疾病的风险更高。然而，由于这些人在晚年往往会保持肥胖，目前还不清楚通过改变生活方式可以在多大程度上逆转这种被赋予的风险。此外，复杂的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独立起作用。这位博士将使用大型数据集来开发多种生活方式因素如何影响疾病风险的推定因果关系图。将重点放在早期生活接触上，因为表明童年时期赋予的风险可以逆转的结果将产生一个重要的可翻译信息，可能影响社会政策。相反，必须更好地了解哪些早期生活风险因素对疾病易感性有不可改变的影响，而这种影响不能通过改变生活方式来缓解。将应用流行病学中一种称为孟德尔随机化(MR)的技术的原理。这种方法使用遗传学来理清因果关系，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，它们对妨碍观测分析的混杂和逆因果关系等因素具有很强的抵抗力。

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.