The Genetic Architecture of Homeostasis in Health

We will look at health in a novel way by identifying body processes that are under tight control and finding genes and genetic variants that affect that control. Body processes that are tightly controlled are under homeostatic control. Homeostasis is important for health, and poor health often reflects a loss of homeostasis of one or more body processes. Quantities that vary around an ideal value in populations show what we call a "sweet spot". If having a close to ideal value for a certain measure (for example, blood pressure) is important for health, then healthy individuals will have measures closer to the sweet spot. Our multi-disciplinary team will use data from a study of 30,000 Canadians in whom 1,300 different quantities have been measured. These measures include 270 physical measures such as blood pressure, bone density, body composition and blood cell counts. In addition, over 1,000 metabolites, or specific molecules, have been measured in their blood; these molecules provide a window into the health and body processes of these individuals. We will analyze these measures mathematically and identify those that show a sweet spot, in which healthier individuals are closer to an ideal value than are less healthy individuals the same age. We have tested these methods using 270 measures, and have identified over 100 quantities that show sweet spots. We propose to use apply these same methods to metabolites. We will then conduct innovative genome-wide genetic studies to identify genetic variants and genes that influence how close an individual's measure is to the sweet spot. We expect to identify hundreds of sweet spots and genetic variants that influence many of them. Given our novel approach on traits related to homeostasis, we expect findings not previously identified through studies focused on specific diseases. The new insights gained will inform lifestyle modifications and development of drugs to preserve the homeostatic condition and health.