Equine metabolic syndrome affects all breeds of horses and ponies and is the leading cause of laminitis, a costly and debilitating disease. Despite $15 million spent annually in the United States on diagnosis and management of this disease, nearly 20% of afflicted animals never fully recover. The near complete lack of understanding of how the environment impacts genetics (GxE) has direct consequences for EMS horses, owners and researchers. Without this knowledge, it is impossible to predict which horses will develop clinical signs, or become severely affected, once exposed to a specific environmental risk factor. EMS horses which do not respond to standard management strategies have a high risk of recurrent laminitis which places a huge cost, time and emotional burden on their owners. Therefore, this represents a missed opportunity to be able to leverage GxE information to modify the genetic risk for disease in an environmental specific manner by creating targeted management plans to improve treatment response rate in refractory individuals. In this proposal, we will identify environmental risk factors influencing EMS genetic risk at multiple levels of the genome. This will be accomplished by (1) identifying genetic risk alleles impacted by the environment; (2) determining gene expression and metabolite factors influenced by the environment; and (3) identifying epigenetic modifications that impact EMS clinical phenotypes. The expected outcome of this proposal is the identification of genetic risk alleles, molecular phenotypes and epigenetic signals associated within known environmental risk factors for EMS.