ArticleAmerican journal of human genetics2004
Melanocortin-4 receptor gene variant I103 is negatively associated with obesity.
Article in American journal of human genetics, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 3 of them syntheses that pooled it.
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Who cites it
78 citing papers in PubMed, 3 syntheses or guidelines pooled it, 214 citations in OpenAlex.
- Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups.PLoS genetics · 2010Pooled it
- The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals.International journal of obesity (2005) · 2007Pooled it
- Meta-analysis on the effect of the N363S polymorphism of the glucocorticoid receptor gene (GRL) on human obesity.BMC medical genetics · 2006Pooled it
- Shared and distinct genetic architectures of eating disorders and obesity: From monogenic causes to polygenic risk.Reviews in endocrine & metabolic disorders · 2026Review
- The Clinical Phenotype and Genetic Analysis of Monogenic Non Syndromic Obesity Caused by MC4R Gene Variation.Molecular genetics & genomic medicine · 2026Article
- Associations of genetic variants in TCF7L2, MC4R, AGT and ACE genes with cardiometabolic diseases in Black South Africans.BMC medical genomics · 2026Article
- Unexpected identification of obesity-associated mutations in LEP and MC4R genes in patients with anorexia nervosa.Scientific reports · 2024Article
- A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.The Journal of clinical investigation · 2024Article
- Genetic variant panel allows predicting both obesity risk, and efficacy of procedures and diet in weight loss.Frontiers in nutrition · 2023Article
- The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits.Nature reviews. Endocrinology · 2022Review
- [Nutrigenetics: potentials and applications in cardiovascular diseases and associated risk factors].Revista de la Facultad de Ciencias Medicas (Cordoba, Argentina) · 2022Article
- Mouse models for V103I and I251L gain of function variants of the human MC4R display decreased adiposity but are not protected against a hypercaloric diet.Molecular metabolism · 2020Article
- Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R).Physiological research · 2020Review
- Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.International journal of molecular sciences · 2020Article
- The Effect Sizes ofGenes · 2020Article
- Article
- Genetic architecture of human thinness compared to severe obesity.PLoS genetics · 2019Article
- Association between LEPR, FTO, MC4R, and PPARG-2 polymorphisms with obesity traits and metabolic phenotypes in school-aged children.Endocrine · 2018Article
- Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
- Allelic variants of the Melanocortin 4 receptor (MC4R) gene in a South African study group.Molecular genetics & genomic medicine · 2016Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.
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