Genetic susceptibility to obesity mediated through eating behaviours

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.