Obesity and Cardiometabolic Disease: Insights From Genetic Studies

Obesity is a highly prevalent chronic disease and major driver of both atherosclerotic heart disease and heart failure. Obesity is also a heritable neuronal disease with heritability estimates of up to 70%. In this work I review how common genetic variants, usually with small effect sizes, contribute to the risk for developing obesity and cardiometabolic disease in the majority of people and how this can be further modulated by environmental factors. In some individuals, rare genetic variants with large effect sizes can influence the risk of developing obesity, in some cases in a Mendelian manner. I also address how identification of these rare variants has led to fundamental biologic insights into how satiety and reward are biologic processes, has led to more personalized treatments, and has identified potential novel drug treatments. Biologic insights derived from genetic studies of obesity have also improved our understanding of the causal mediators between obesity and cardiovascular disease. A major limitation of studies to date is that they involved mostly people of European ancestry. Studying more diverse populations will improve our understanding of obesity and cardiometabolic disease. Lessons derived from genetic studies make a compelling case for increasing accessibility to therapies that have sustained efficacy in managing obesity and improving health. This increased knowledge must also inform public health initiatives that will reduce the prevalence of obesity in the coming decades.