Genetic susceptibility to obesity mediated through eating behaviours

概述：我们知道肥胖的遗传风险在一定程度上是通过饮食行为的改变来调节的，比如增加了去抑制作用(缺乏对饮食的控制)，但我们不知道是如何发生的。该项目分析了现有的队列数据，并使用新的神经成像实验来检查BMI的遗传风险是否通过进食行为通过对食物的神经和行为反应来调节。更详细：解决肥胖流行病是我们最紧迫的全球健康挑战之一。在英国，%的成年人超重或肥胖，暴饮暴食是一个关键因素。BMI是高度可遗传的，已经与600多个基因相关。该项目研究体重指数(BMI-GRS)的遗传风险分数与(过量)进食行为之间的联系，为制定更有针对性和更有效的预防和治疗提供信息。BMI-GRS的调节机制涉及大脑机制和特定进食行为的变化，即儿童和成人的饥饿增加和去抑制(对饮食缺乏控制)。在横断面和纵向研究中，这些行为也与BMI和减肥效果不佳有关。该项目旨在通过i)对现有队列数据进行高级统计分析以及ii)使用一直与BMI相关的神经成像和行为测量来检查选定个体的中间表型，从而发现饮食行为如何调节肥胖的遗传易感性。两个子项目将为成功的学生提供补充和非常受欢迎的量化技能的跨学科培训：1)遗传队列数据的统计分析(0-36个月)：对我们有其饮食行为评分和BMI-GRS的2个本地队列的数据进行二级分析。我们的BMI-GRS是独一无二的，也是迄今为止最敏感的，基于共同监督人Frayling最近发现的620个基因座的加权总和。我们有2713名中年人(男性=59.3岁)在埃克塞特和约4400名年轻人(26-27岁)在ALSPAC(布里斯托尔)的数据。早期的发现重复了BMI-GRS和饮食行为之间的联系。学生将进行二次分析，以检查与饮食行为和这些丰富数据集中的其他关键变量(例如，饮食、食物偏好和儿童饮食行为)之间的关系。2)检查中介肥胖遗传易感性的中间神经和行为表型(36-72个月)：按基因回忆的设计将检查BMI-GRS和饮食行为对对食物暗示和饱腹感的有效行为和神经成像反应的影响。表型包括fMRI(纹状体和脑岛感兴趣区)的食物提示反应性，食物的喜好/摄入量，以及在味觉测试和验证的计算机任务中对饱腹感的反应。我们将比较在性别、年龄和BMI方面匹配的高BMI-GRS和低BMI-GRS(每组50人)。回归将决定BMI-GRS如何影响神经和行为对食物/饱腹感的反应，作为主要影响因素，并与饮食行为得分相互作用。这一博士学位建立在埃克塞特和布里斯托尔在肥胖遗传学和心理学方面的优势之上，并利用我们独特的能力，从当地的遗传队列中召回成年人，以更详细地研究与进食行为/对食物的反应相关的表型。从2019年开始，埃克塞特将拥有与布里斯托尔相同的3T磁共振扫描仪，促进多部位神经成像。

Overview: We know that genetic risk for obesity is partly mediated through changes in eating behaviours such as increased disinhibition (a lack of control over eating) but we don't know how. This project analyses existing cohort data and uses new neuroimaging experiments to examine whether genetic risk for BMI is mediated through eating behaviours via neural and behavioural responses to food.More detailed: Tackling the obesity epidemic is one of our most urgent global health challenges. In the UK 64% of adults are overweight or obese, with overeating a key factor. BMI is highly heritable and has been associated with over 600 genes. This project examines the link between genetic risk scores for BMI (BMI-GRS) and (over)eating behaviours to inform the development of more targeted and effective prevention and treatment. The mechanisms mediating BMI-GRS involve brain mechanisms and changes in specific eating behaviours, namely increased hunger and disinhibition (a lack of control over eating) in children and adults. These behaviours are also associated with BMI and poor weight loss in cross-sectional and longitudinal studies. This project aims to discover how eating behaviours mediate genetic susceptibility to obesity by i) conducting advanced statistical analyses of existing cohort data and ii) examining intermediate phenotypes in selected individuals using neuroimaging and behavioural measures that have been consistently associated with BMI. Two sub-projects will provide the successful student with cross-disciplinary training in complementary and highly sought-after quantitative skills: 1) Statistical analysis of genetic cohort data (0-36 months): Secondary analyses of data from 2 local cohorts for whom we have eating behaviour scores and BMI-GRS. Our BMI-GRS is unique and the most sensitive to date, based on the weighted sum of 620 loci recently discovered by co-supervisor Frayling. We have data in 2713 middle-aged adults (M=59.3 years) in Extend (Exeter) and in ~4400 young adults (aged 26-27) in ALSPAC (Bristol). Early findings replicate the associations between BMI-GRS and eating behaviours. The student will conduct secondary analyses to examine associations with eating behaviours and other key variables in these rich datasets (e.g. diet, food preference and childhood eating behaviours). 2) Examination of intermediate neural and behavioural phenotypes mediating genetic susceptibility to obesity (36-72 months): A recall-by-genotype design will examine the impact of BMI-GRS and eating behaviours on validated behavioural and neuroimaging responses to food cues and satiety. Phenotypes include food cue-reactivity in fMRI (striatal and insula regions-of-interest) and food liking/intake and responses to satiety in taste tests and validated computer tasks. We will compare recalled adults with high vs. low BMI-GRS (N=50 per group) matched for sex, age and BMI. Regressions will determine how BMI-GRS affects neural and behavioural responses to food/satiety as a main effect and in interaction with eating behaviour scores. This PhD builds on Exeter and Bristol's strengths in the genetics and psychology of obesity and capitalises on our unique ability to recall adults from local genetic cohorts for more detailed examination of phenotypes related to eating behaviour/responses to food. From 2019, Exeter will have the same 3T MRI scanner as Bristol, facilitating multi-site neuroimaging.