Genetics of Obesity: What We Have Learned Over Decades of Research

There is a genetic component to human obesity that accounts for 40% to 50% of the variability in body weight status but that is lower among normal weight individuals (about 30%) and substantially higher in the subpopulation of individuals with obesity and severe obesity (about 60%‐80%). The appreciation that heritability varies across classes of BMI represents an important advance. After controlling for BMI, ectopic fat and fat distribution traits are characterized by heritability levels ranging from 30% to 55%. Defects in at least 15 genes are the cause of monogenic obesity cases, resulting mostly from deficiencies in the leptin‐melanocortin signaling pathway. Approximately two‐thirds of the BMI heritability can be imputed to common DNA variants, whereas low‐frequency and rare variants explain the remaining fraction. Diminishing allele effect size is observed as the number of obesity‐associated variants expands, with most BMI‐increasing or ‐decreasing alleles contributing only a few grams or less to body weight. Obesity‐promoting alleles exert minimal effects in normal weight individuals but have larger effects in individuals with a proneness to obesity, suggesting a higher penetrance; however, it is not known whether these larger effect sizes precede obesity or are caused by an obese state. The obesity genetic risk is conditioned by thousands of DNA variants that make genetically based obesity prevention and treatment a major challenge.