Gain‐of‐function variants in the melanocortin 4 receptor gene confer susceptibility to binge eating disorder in subjects with obesity: a systematic review and meta‐analysis

Abstract

Summary The association between coding variants in the melanocortin 4 receptor gene (MC4R) and binge eating disorder (BED) in patients with obesity is controversial. Two independent reviewers systematically searched MEDLINE, Embase, PsycINFO, BIOSIS Previews, Web of Science Core Collection and Google Scholar up to February 2018, using terms describing the MC4R gene and BED. Six of 103 identified references were included. Studies examined associations between at least one coding variant/mutation in MC4R and BED and screened for BED as per the Diagnostic and Statistical Manual of Mental Disorders. Risk of bias was assessed using a modified version of the Q‐Genie tool, and overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation guidance. Meta‐analysis was conducted via logistic regression models. A positive association between gain‐of‐function (GOF) variants in the MC4R and BED was observed (odds ratio [OR] = 3.05; 95% confidence interval [CI]: 1.82, 5.04; p = 1.7 × 10−5), while no association was detected between loss‐of‐function (LOF) mutations and BED (OR = 1.50; 95% CI: 0.73, 2.96; p = 0.25). Similar results were found after accounting for study quality (GOF variants: OR = 3.15; 95% CI: 1.76, 5.66; p = 1.1 × 10−4; LOF mutations: OR = 1.50; 95% CI: 0.73, 2.97; p = 0.25). Our systematic review and meta‐analysis provides evidence that GOF variants as opposed to LOF mutations in MC4R are associated with BED in subjects with obesity.

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

“…Because of oligogenic effects of MC3R mutations on obesity, to date, no single study has been sufficiently powered to provide a definitive answer. We opted to employ a pooled meta‐analytic approach as previously described rather than the standard meta‐analysis because of low numbers or absence of rare coding partial/complete LOF mutations carriers reported in the included case and control groups of the current review. This allowed us to investigate the association between rare coding partial/complete LOF mutations in MC3R and obesity with enhanced statistical power.…”

“…The risk of bias for individual studies was assessed using the tool recently developed by our team . Though no serious risk of bias was found in the studies included in the systematic review, the quality of evidence of each of the study was considered low according the GRADE assessment because of the non‐randomized study design.…”

“…The odds ratio (OR) of obesity among partial/complete LOF mutation carriers, compared with individuals without functionally relevant coding mutations in MC3R was determined via meta‐analysis. Similar to our previous meta‐analysis of rare variant association studies of melanocortin receptor 4 gene and binge eating disorder, three of the studies did not find any rare coding LOF variants of MC3R in the participants with normal weight. In order to avoid traditional 0.5 correction factor added to zero cells that can severely bias the result of rare event studies, we pooled the results of all included studies of the current systematic review to calculate a single effect estimate in lieu of calculating crude ORs and 95% confidence intervals (CIs) for each study (Table S2).…”

“…Risk of bias was assessed independently by two reviewers (SE and AQ) using the tool (Table S3) previously developed based on limited guidance in rare genetic variant association studies, expert opinion, the Q‐Genie (quality of genetic association studies), and the ROBINS‐I tool . Each of the six domains (selection bias, bias because of confounding, bias in classification of exposure, bias in assessment of outcome, bias because of missing data, and bias in selection of reported results) received rating of “low risk,” “probably low risk,” “probably high risk,” and “high risk.” Final risk of bias ratings for each of the study was determined through consensus or by referring to a third reviewer (DM), as needed.…”

Systematic Review and Meta-Analysis of Candidate Gene Association Studies With Fracture Risk in Physically Active Participants

“…(3) genetic variant(s). Quality assessment and risk of bias assessments were carried out using the Q-Genie (Sohani et al, 2015) and modified ROBINS-I (Sterne et al, 2016;Qasim et al, 2019) tools independently by two authors (ERM and YM). The Q-Genie tool categorizes studies as either poor, moderate, or good quality with the modified ROBINS-I determining risk of bias as low, moderate, serious, or critical.…”