Precision Medicine for Obesity: Genetic Subtypes and Their Distinct Risk Profiles

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Summary of Nature Medicine. https://dx.doi.org/10.1038/s41591-025-03931-0 
Dr. Nathalie Chami et al.

Points

Researchers performed a multi-trait genome-wide association analysis on 452,768 UK Biobank participants.
The study identified 266 genetic variants where increased adiposity correlated with lower cardiometabolic risk.
A genetic risk score from these variants showed reduced risk for dyslipidemia and ischemic heart disease.
Eight distinct genetic subtypes of obesity were identified, each with unique risk profiles.
Proteomic analyses further differentiated adiposity-driven effects from health-driven effects.

Summary

This study conducted a comprehensive multi-trait genome-wide association analysis (GWAS) using individual-level data from 452,768 UK Biobank participants to explore the genetic mechanisms that uncouple adiposity from cardiometabolic comorbidities. Researchers defined continuous ‘uncoupling phenotypes’ that ranged from individuals with high adiposity but healthy cardiometabolic profiles to those with low adiposity yet unhealthy profiles. The analysis focused on three adiposity traits (BMI, body fat percentage (BFP), waist-to-hip ratio (WHR)) and eight cardiometabolic traits (total cholesterol, LDL-C, HDL-C, triglycerides, random glucose, HbA1c, systolic blood pressure (SBP), and diastolic blood pressure (DBP)). This approach identified 266 unique lead variants across 205 genomic loci where alleles increasing adiposity were simultaneously associated with a lower risk of at least one cardiometabolic trait. Of these, 139 loci had not been previously reported in this context.

A genetic risk score (GRSuncoupling), constructed from these 266 variants, demonstrated an association with a lower risk of several cardiometabolic disorders. Specifically, a higher GRSuncoupling was linked to reduced levels of LDL-C, TC, TG, HbA1c, glucose, SBP, and DBP, along with higher HDL-C, despite being associated with higher overall adiposity. In contrast, a GRS based solely on BFP-associated variants (GRSBFP) was associated with an increased risk for many of these same cardiometabolic traits. Furthermore, GRSuncoupling was associated with a more favorable fat distribution, including lower MRI-derived visceral adipose tissue to abdominal subcutaneous adipose tissue ratio, trunk fat to gluteofemoral fat ratio, and liver fat fraction, unlike GRSBFP.

A phenome-wide association analysis (PheWAS) in 373,747 UK Biobank participants revealed that while GRSuncoupling was associated with a lower risk of dyslipidemia (OR=0.92, P=1.4×10−89), essential primary hypertension (OR=0.96, P=1.7×10−27), noninsulin-dependent diabetes (OR=0.94, P=5.6×10−21), and ischemic heart disease (OR=0.96, P=7.4×10−11), it also showed an increased risk for weight-bearing diseases such as cellulitis (OR=1.05, P=1.14×10−11), gonarthrosis (OR=1.06, P=9.9×10−25), and varicose veins (OR=1.08, P=7.9×10−26), similar to GRSBFP. These findings highlight novel genetic mechanisms that can uncouple obesity from its cardiometabolic complications and establish a basis for genetically informed obesity subtyping, supporting precision medicine approaches.

Link to the article: https://www.nature.com/articles/s41591-025-03931-0

References

Chami, N., Wang, Z., Svenstrup, V., Obrero, V. D., Hemerich, D., Huang, Y., Dashti, H., Manitta, E., Preuss, M. H., North, K. E., Holm, L. A., Fonvig, C. E., Holm, J.-C., Hansen, T., Scheele, C., Rauch, A., Smit, R. A. J., Claussnitzer, M., & Loos, R. J. F. (2025). Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities. Nature Medicine, 1–12. https://doi.org/10.1038/s41591-025-03931-0