Using genetics to test the disease consequences of higher adiposity uncoupled from its adverse metabolic effects

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Obesity is associated with many diseases in addition to type 2 diabetes and heart disease. People who are carrying too much weight are also at greater risk of diseases of the joints (e.g. osteoarthritis) , gut and intestinal tract (e.g. gastro-oesophageal reflux disease, diverticular disease), diseases of mental health (e.g. depression) and some cancers (e.g. post-menopausal breast cancer). For many of these conditions, we do not know if being overweight is a cause or is simply correlated due to shared factors such as ageing and poor general health. Even if we do know that being overweight is a direct cause, we do not know which aspect of the excess fat mass is important. For example, for a disease of the joints, such as osteoarthritis, the excess weight itself could be more important or the inflammation that normally accompanies excess weight could be more important, in causing the disease. In this proposal, we aim to understand the causal effects of two separate aspects of being overweight on common diseases - the excess fat, and the adverse consequences that normally accompany excess fat. These adverse consequences include reduced sensitivity to the beneficial effects of insulin, higher levels of fat and cholesterol in the blood, and inflammation. We will use a novel genetic approach where we characterise two sets of genetic variants - those associated with "normal fat" and those associated with "favourable fat". The "normal fat" genetic variants are associated with more fat and higher risk of metabolic diseases such as type 2 diabetes. The "favourable fat" variants are associated with more fat but lower risk of metabolic diseases. We will then compare the effects of these two sets of genetic variants on non-metabolic diseases using very large datasets such as the UK Biobank and other large collections of 10,000s of people with and without diseases. If both the normal and favourable fat genetic variants are associated with risk of a disease such as osteoarthritis, it will indicate the excess weight is important. In contrast, if only the "normal fat" genetic variants are associated, it will indicate the adverse metabolic consequences are more important. Diseases we will study include osteoarthritis, gastro-oesophageal reflux, depression, osteoporosis, breast cancer and psoriasis.Understanding the mechanism by which excess weight causes conditions such as osteoarthritis and reflux disease is of fundamental importance to developing effective interventions and treatments. For example if excess weight is shown to cause a condition purely through the adverse metabolic effects, this raises the possibility of treatments that modify the metabolic effects, such as inflammation or insulin sensitivity. If effects are purely driven by the excess weight itself, these approaches will be futile.