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，比如抑制作用的增强（对饮食缺乏控制），但我们不知道如何调节。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对食物的神经和行为反应通过饮食行为介导。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，64%的成年人超重或肥胖，暴饮暴食是一个关键因素。BMI具有高度遗传性，与600多个基因有关。该项目研究了BMI （BMI- grs）遗传风险评分与（过度）饮食行为之间的联系，为更有针对性和更有效的预防和治疗提供信息。调节BMI-GRS的机制涉及大脑机制和特定饮食行为的变化，即儿童和成人的饥饿感增加和抑制解除（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。该项目旨在通过对现有队列数据进行高级统计分析和ii)使用与BMI一致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介导对肥胖的遗传易感性。两个子项目将为成功的学生提供跨学科的互补和高度抢手的定量技能培训：1)遗传队列数据的统计分析（0-36个月）：对两个本地队列的数据进行二次分析，我们有饮食行为评分和BMI-GRS。基于Frayling最近发现的620个基因座的加权和，我们的BMI-GRS是唯一的，也是最敏感的。我们收集了Extend（埃克塞特）2713名中年人（M=59.3岁）和ALSPAC（布里斯托尔）约4400名年轻人（26-27岁）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，以检查与这些丰富数据集中的饮食行为和其他关键变量（例如饮食，食物偏好和儿童饮食行为）的关联。2)检查介导肥胖遗传易感性的中间神经和行为表型（36-72个月）：通过基因型回忆设计将检查BMI-GRS和饮食行为对食物线索和饱腹感的有效行为和神经影像学反应的影响。表型包括fMRI（纹状体和脑岛感兴趣区）中的食物线索反应性，以及味觉测试和验证计算机任务中的食物喜好/摄入和对饱腹感的反应。我们将比较与性别、年龄和BMI相匹配的高BMI- grs和低BMI- grs的被召回成年人（每组N=50）。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，并与饮食行为评分相互作用。该博士学位建立在埃克塞特大学和布里斯托尔大学在肥胖遗传学和心理学方面的优势之上，并利用我们从当地遗传队列中回忆成年人的独特能力，对与饮食行为/食物反应相关的表型进行更详细的研究。从2019年开始，埃克塞特将拥有与布里斯托尔相同的3T MRI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.