Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.

Summary

Using WGS in 88,873 TOPMed participants (51% non-European), the authors identified 18 BMI-associated loci, including a novel risk allele specific to African ancestry, demonstrating the power of sequencing beyond imputation. This work addresses ancestry bias in obesity genetics and strengthens the foundation for ancestry-aware risk prediction and mechanistic follow-up.

Key Findings

• Whole-genome sequencing of 88,873 TOPMed participants (51% non-European) identified 18 BMI-associated signals.
• Discovery of a novel African ancestry-specific risk allele for BMI, addressing Eurocentric biases of prior GWAS.
• Sequencing-based approach demonstrated added value over imputation-based analyses for locus discovery.

Clinical Implications

Immediate clinical practice change is limited, but findings will inform ancestry-tailored polygenic risk scores, guide functional studies toward therapeutic targets, and improve external validity of obesity risk prediction across populations.

Limitations

• Observational genetic association without direct functional validation of identified variants.
• Effect estimates and fine-mapping details are not provided in the abstract; clinical translation requires further work.

Future Directions

Functionally characterize the African ancestry-specific allele and other loci, integrate multi-omics to map causal mechanisms, and develop/validate ancestry-aware polygenic risk scores for clinical use.