Obesity is a major global health issue arising from a combination of environmental factors and genetic predisposition. Research highlights the significance of the leptin-melanocortin pathway in monogenic obesity; rare early-onset (age <5 years) obesity caused by a single variant. Genome-wide association studies (GWAS) suggest that the same genes play a role in common polygenic obesity. This study investigates the impact of single variants within this pathway and their cumulative effect, in form of a polygenic risk score (PRS). We analyzed how these genetic variations influence Body Mass Index (BMI), Waist-Hip Ratio (WHR), and overall obesity prevalence in the general population.

We used the population-based cohort from the Rotterdam Study (n=10494). BMI is measured in kg/m² and obesity is defined as BMI>30 with subclasses; class 1 (≥30BMI<35), class 2 (≥35BMI<40) and class 3 (BMI>40). From the summary statistics of the 2018 GIANT BMI GWAS, 16 out of 941 variants were mapped to 8 genes of the leptin-melanocortin pathway (LEPR, SH2B1, PCSK1, NPY, MC4R, GNB1, ADCY3, BDNF), which were used to calculate the weighted PRS (LMP-PRS). All models were adjusted for age and sex.

LMP-PRS was associated with BMI explaining 0.3% of the BMI variance compared to 4.1% by the full PRS, consisting of 941 variants. In addition, the LMP-PRS was significantly associated with an increased risk of obesity (OR=1.16, P=7.8e-7). Stratification for the obesity subclasses showed that the LMP-PRS yielded the highest risk for OCIII (OCI: OR=1.13, P=1.4e-4: OCII: OR=1.18, P=5.5e-3; and OCIII: OR=1.43, P=2.3e-3). Individuals in the top 1% LMP-PRS have a 2.45 higher risk for obesity compared to the middle 50% of the LMP-PRS distribution (P=1.3e-3). No significant association was found between LMP-PRS and WHR.

To conclude, the leptin-melanocortin pathway also plays a role in common obesity, explaining 7% of the total variance explained of BMI by genetic variants. Ongoing studies will determine if carriers of the LMP-PRS also have an increased risk of obesity-associated comorbidities.