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

Abstract

Summary 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.

Sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in panels of monogenic obesity genes from the leptin‐melanocortin pathway: A systematic review

“…In brief, penetrance of obesity was complete in homozygous mutation carriers and varied from incomplete to complete in heterozygous carriers, in line with literature 39 . Contrary to other monogenic diseases with complete penetrance (e.g., cystic fibrosis), the penetrance of monogenic obesity genes on obesity depends on many factors such as heterozygous/homozygous status, inheritance model, sex, age, ethnicity, epistasis, and interactions with the environment 74 . Penetrance is required for defining the risk of obesity associated with monogenic obesity genes in a translational perspective 39,75 …”

“…39 Contrary to other monogenic diseases with complete penetrance (e.g., cystic fibrosis), the penetrance of monogenic obesity genes on obesity depends on many factors such as heterozygous/ homozygous status, inheritance model, sex, age, ethnicity, epistasis, and interactions with the environment. 74 Penetrance is required for defining the risk of obesity associated with monogenic obesity genes in a translational perspective. This study presents several limitations.…”

The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

“…Mutations in MC3R , which are rare, have also been linked to obesity [29]. For example, a recent meta-analysis of 2,969 individuals with obesity and 2,572 with normal weight confirmed that loss-of-function mutations in this gene increase the risk for obesity [30]. In our present study we identified one MC3R variant (c.920C>A; p.R307H) in an obese subject (BMI 39 kg/m 2 ).…”

Charge Characteristics of Agouti-Related Protein Implicate Potent Involvement of Heparan Sulfate Proteoglycans in Metabolic Function

“…The central melanocortin system includes neurons in the arcuate nucleus (ARC) of the hypothalamus that coexpress agouti-related protein (AgRP) and neuropeptide Y (NPY) and the neurotransmitter γ-aminobutyric acid (GABA) and neurons that coexpress proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART; van der Klaauw, 2018). Evidence from mutant mice and human mutations indicates that the central melanocortin system plays a key role in coordinating nutrient intake, energy metabolism, fat accumulation, and body weight (Butler et al., 2000, Chen et al., 2000, Ehtesham et al., 2019, Lede et al., 2016, Nuutinen et al., 2018). However, the contribution of AgRP to metabolic regulation is not well understood because of its coexpression with GABA (Krashes et al., 2013) and NPY, which is also a key regulator of appetite and energy balance (Loh et al., 2015).…”

“…NPY/AgRP neurons mediate insulin's central effects on hepatic glucose production (Konner et al., 2007, Obici et al., 2002, Pocai et al., 2005). Fat accumulation and obesity comprise the primary phenotype of lower central melanocortin-3 receptor (MC3R) and MC4R loss-of-function (Butler et al., 2000, Chen et al., 2000, Ehtesham et al., 2019, Lede et al., 2016, Nuutinen et al., 2018). Insulin receptor signaling in NPY/AgRP neurons in the ARC inhibits hepatic glucose production via vagus nerves that are associated with food intake (Konner et al., 2007, Obici et al., 2002, Pocai et al., 2005).…”