The expanding landscape of genetic causes of obesity

Obesity and weight regulation disorders are determined by the combined effects of genetics and environment. Polygenic obesity results from the combination of common variants in several genes which predisposes the individual to obesity and its related complications. In contrast, monogenic obesity results from changes in single genes, especially those in leptin-melanocortin pathway, and presents with early onset severe obesity, with or without other syndromic features. Rare variants in melanocortin 4 receptor are the commonest form of monogenic obesity. In addition, structural variation in small or large segments of chromosomes may also present with syndromic forms of obesity. Prader-Willi Syndrome, caused by imprinting errors in chromosome 15q11-13, is the most prevalent genetic cause of severe hyperphagia and obesity. With the advances in technologies, the past decade has witnessed a revolution in the identification of novel genetic causes of obesity, primarily in genes related to the leptin melanocortin pathway. The availability of safe melanocortin analogs holds the potential for targeted therapies for some of these disorders. This review summarizes known and novel rare genetic forms of obesity, along with approaches for the clinical investigation of copy number and sequence variants. The goal is to provide a reference for practicing clinicians to encourage genetic testing in obesity. IMPACT: What does this article add to the existing literature? Genetic obesity is an expanding frontier with potential to change management. Here, we summarize current information on the genetic causes of obesity and provide guidance for genetic testing. Emerging treatments may provide targeted precise treatment and change management practices.