The genetics of obesity: aetiology, prevention and therapy

Obesity is a complex, multifactorial condition with a strong genetic basis, encompassing monogenic, oligogenic and polygenic contributions. More than 1 billion people worldwide have obesity, including 150 million children. Since the discovery of leptin, over 85 monogenic forms have been identified, characterized by early-onset obesity with impaired appetite regulation, usually associated with neurodevelopmental (and other) phenotypes, making monogenic obesity mostly syndromic. However, genome-wide association studies have identified over 1,000 loci associated with weight variation. Advances in human genetics have translated into innovative therapeutic strategies. In particular, melanocortin 4 receptor agonists illustrate how genetic discoveries can target treatments, paving the way for precision medicine in obesity. These advances offer new opportunities to tailor treatments to the underlying genetic causes. In this Review, we highlight how genetic discoveries have deepened our understanding of obesity pathophysiology and accelerated precision medicine, and we discuss future strategies to enhance prevention and personalize patient care based on genetic background.