Association of Mutations in the Melanocortin-2 Receptor Accessory Protein 2 Gene (MRAP2) and Obesity: A Systematic Review and Meta-Analysis

Melanocortin-2 receptor accessory protein 2 (MRAP2) is essential for the intricate regulation of energy balance. Although rare <i>MRAP2</i> variants have been reported in obese individuals, their overall impact on human obesity risk remains uncertain because previous studies were small, heterogeneous, and often lacked systematic functional characterization. To address this gap, we conducted a comprehensive systematic review and cohort-level meta-analysis to quantify the association between rare coding variants in <i>MRAP2</i> and obesity. We systematically searched five major databases (Embase, PubMed, Scopus, Google Scholar, and Web of Science) and identified five eligible publications comprising seven independent cohorts. In total, 27 rare coding <i>MRAP2</i> variants were observed in 46 (1.01%) individuals with obesity and 18 (0.34%) individuals with normal weight, among 9771 individuals (5223 with normal weight and 4548 with obesity). Using inverse-variance-weighted random-effects models fitted with restricted maximum likelihood, carriers of rare coding <i>MRAP2</i> variants had higher odds of obesity (OR = 2.61; 95% CI, 1.49-4.58; <i>p</i> = 8.0 × 10^-4). Taken together, these findings, derived predominantly from European-ancestry cohorts, support MRAP2 as a biologically plausible susceptibility gene for human obesity and indicate that rare coding <i>MRAP2</i> variants are associated with higher odds of obesity, providing a quantitative framework to guide future large-scale genetic and functional studies.