Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, Bristol, BS8 2BN, UK.
Nat Commun. 2022 Aug 11;13(1):4726. doi: 10.1038/s41467-022-32183-6.
Alzheimer's disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.
阿尔茨海默病（AD）目前尚无明确的病因和可改变的风险因素，也没有有效的干预措施。我们在 UK Biobank 研究的 334968 名参与者中进行了一项 AD 遗传易感性的全表型关联研究（PheWAS），并按年龄进行分层。我们还研究了 AD 遗传易感性对先前涉及的风险因素的影响。我们在 HUNT 研究中对这些分析进行了复制。在孟德尔随机化（MR）框架中，对 PheWAS 命中和先前涉及的风险因素进行了随访，以确定每个风险因素对 AD 风险的因果效应。AD 遗传易感性越高，与 39 岁时的病史以及认知、生活方式、身体和血液相关测量值的关联就越大。这些影响主要是由 APOE 基因驱动的。后续的 MR 分析主要为阴性，这意味着这些关联中的大多数很可能是前驱疾病或选择偏倚的结果，而不是风险因素导致疾病。
