Approved research

Investigating genetic basis for causal role of adiposity with type2 diabetes, non-alcoholic fatty liver diseases, and Alzheimer's disease

Lay summary

Rationale: Complex human disease like, type 2 diabetes (T2D), cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and Alzheimer's dementia (AD), are caused by genetic variations in more than one gene as well as environmental contributions. Adiposity, including both higher body mass index and central obesity is a growing health problem, and often co-occurs with or predisposes individuals to the above-mentioned conditions. However, epidemiological studies cannot provide much information on causality of adiposity to the related metabolic and neurodegenerative conditions is not clear, due to limitations involving confounders and reverse causality. We aim to investigate the genetic basis of the causal relationship of adiposity to T2D, NAFLD, AD. We will use Mendelian Randomization (MR), an approach that is not biased by reverse causation or confounders to evaluate whether BMI and central obesity increases risk of T2D, NAFLD, AD. The causality inference can be drawn because genetic variants are asserted to be free from conventional confounding due to the random independent assortment of DNA during meiotic segregation of alleles. Also, the transmitted germline variations are of non-modifiable nature, so reverse causality can be ruled out. Aims: In this project, we will perform the GWAS for adiposity measured by BMI, central adiposity measured by waist to hip ratio adjusted for BMI, related metabolic disorders- type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and neurodegenerative diseases, like Alzheimer's disease (AD). Thereafter, we aim to identify the causal relationship of adiposity with T2D, NAFLD, AD using Mendelian randomization. Here, adiposity is the exposure of interest and T2D/NAFLD/AD is the health outcome of interest in separate MR analyses. Genetic variants that influence adiposity are used as instrumental variables to obtain an unbiased estimate of the causal effect that adiposity has on T2D/ NAFLD/ AD. This project, therefore, aims to determine if genetic susceptibility to general or central obesity are causal risk factors for certain metabolic and neurodegenerative disorders. Project duration: 36 months. Public health: Epidemiological studies cannot provide much information for causality due to limitations involving confounders and reverse causality. Understanding how genetic predisposition to adiposity can be causal risk factors for related metabolic and neurodegenerative diseases- would facilitate targeted weight loss interventions aimed at delaying or preventing the onset of such conditions.