Loss-of-function mutations in the melanocortin-3 receptor gene confer risk for human obesity: A systematic review and meta-analysis.

ABSTRACT

The association between rare coding loss-of-function (LOF) mutations in the melanocortin receptor 3 (MC3R) gene and human obesity is controversial. To fill this gap of knowledge, we performed a systematic review and meta-analysis of genetic association studies in all ages and ethnicities. Two reviewers independently performed risk of bias assessment and extracted data. We searched Medline, Embase, Web of Science Core Collection, BIOSIS Preview, CINAHL, ProQuest Dissertations & Theses, and reference lists of relevant studies. All case-control, cross-sectional, prospective, and retrospective studies that evaluated prevalence of rare (less than 1% frequency) coding partial/complete LOF mutations in MC3R among individuals with obesity and normal weight were included. Our systematic search identified 1925 references relevant to the present review. Six studies were deemed eligible. Meta-analysis of 2969 individuals with obesity and 2572 with normal weight showed a positive association between rare heterozygous coding partial/complete LOF mutations in MC3R and obesity in children and adults of European, North African, and Asian ancestries (odds ratio = 3.07; 95% CI, 1.48-7.00; P = 4.2 × 10-3 ). Our data demonstrates that rare partial/complete LOF mutations in the coding region of MC3R confer three-time increased risk of obesity in humans, and implies that rare genetic variants with intermediate effects contribute to the missing heritability of obesity.