The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population

Background Melanocortin 4 receptor (MC4R) deficiency, caused by mutations inMC4R, is the most common cause of monogenic forms of obesity. However, these mutations have often been identified in small-scale, case-focused studies. Here, we assess the penetrance of previously reportedMC4Rmutations at a population level. Furthermore, we examine why some carriers of pathogenic mutations remain of normal weight, to gain insight into the mechanisms that control body weight. Methods and findings We identified 59 known obesity-increasing mutations inMC4Rfrom the Human Gene Mutation Database (HGMD) and Clinvar. We assessed their penetrance and effect on obesity (body mass index [BMI] >= 30 kg/m(2)) in >450,000 individuals (age 40-69 years) of the UK Biobank, a population-based cohort study. Of these 59 mutations, only 11 had moderate-to-high penetrance and increased the odds of obesity by more than 2-fold. We subsequently focused on these 11 mutations and examined differences between carriers of normal weight and carriers with obesity. Twenty-eight of the 182 carriers of these 11 mutations were of normal weight. Body composition of carriers of normal weight was similar to noncarriers of normal weight, whereas among individuals with obesity, carriers had a somewhat higher BMI than noncarriers (1.44 +/- 0.07 standard deviation scores [SDSs] +/- standard error [SE] versus 1.29 +/- 0.001,P= 0.03), because of greater lean mass (1.44 +/- 0.09 versus 1.15 +/- 0.002,P= 0.002). Carriers of normal weight more often reported that, already at age 10 years, their body size was below average or average (72%) compared with carriers with obesity (48%) (P= 0.01). To assess the polygenic contribution to body weight in carriers of normal weight and carriers with obesity, we calculated a genome-wide polygenic risk score for BMI (PRSBMI). The PRS(BMI)of carriers of normal weight (PRSBMI= -0.64 +/- 0.18) was significantly lower than of carriers with obesity (0.40 +/- 0.11;P= 1.7 x 10(-6)), and tended to be lower than that of noncarriers of normal weight (-0.29 +/- 0.003;P= 0.05). Among carriers, those with a low PRSBMI(bottom quartile) have an approximately 5-kg/m(2)lower BMI (approximately 14 kg of body weight for a 1.7-m-tall person) than those with a high PRS (top quartile). Because the UK Biobank population is healthier than the general population in the United Kingdom, penetrance may have been somewhat underestimated. Conclusions We showed that large-scale data are needed to validate the impact of mutations observed in small-scale and case-focused studies. Furthermore, we observed that despite the key role ofMC4Rin obesity, the effects of pathogenicMC4Rmutations may be countered, at least in part, by a low polygenic risk potentially representing other innate mechanisms implicated in body weight regulation. Author summaryWhy was this study done? Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, chronic kidney disease, and many cancers. The melanocortin 4 receptor () plays an important role in regulating energy balance and satiety. Mutations in , although rare (<1% of the population), represent the commonest cause of extreme early onset obesity. Mutations in have been identified predominantly in small-scale studies of individuals with obesity. The mutations' impact on obesity risk in the general population remains to be studied. Furthermore, it is not clear why some carriers of mutations maintain a normal weight, even when the mutation was shown to increase risk of obesity. What did the researchers do and find? For 59 mutations previously reported to possibly cause obesity, we determined how many individuals, of a large-scale, population-based cohort ( > 450,000), carried the obesity-increasing allele and how many of these carriers had obesity (i.e., penetrance of mutation). For 11 of these mutations, the penetrance of obesity was high. Of the 182 individuals who carried at least one of these 11 mutations, 154 (85%) individuals had obesity/overweight, whereas 28 (15%) individuals were of normal weight. We observed that, compared with carriers who had obesity, the 28 carriers of normal weight have other inherited genetic variants that overall predispose them to a lower body weight, which may offset the risk caused by the mutation they carry. What do these findings mean? Our findings show that large-scale population data are needed to more accurately assess the impact of mutations on extreme early onset obesity. We show that the obesity-increasing effect of mutations may be mitigated by a low overall genetic susceptibility to obesity. These findings show that body weight is the result of an intricate interplay between rare mutations that have a large impact on obesity, as well as an overall genetic susceptibility determined by common genetic variants each with small effects.