Using genetics to uncouple higher adiposity from its adverse metabolic effects and understand its role in metabolic and non-metabolic disease

To understand the consequences of higher adiposity uncoupled from its adverse metabolic effects, we selected 37 diseases associated with obesity and genetic variants associated with different aspects of excess weight including metabolically “favourable adiposity” (FA) and “unfavourable adiposity” (UFA). Mendelian randomisation (MR) identified two sets of diseases. First, 12 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here MR with the FA and UFA genetics showed opposing effects on the risk of disease, including colorectal and ovarian cancer, and gout. Second, 7 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) is likely a cause. Here MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, were both associated with higher disease risk, including osteoarthritis and venous thromboembolism. Individuals with high BMI are at higher risk of some diseases despite being relatively metabolically healthy.