A meta-analysis and polygenic score study identifies novel genetic markers for waist-hip ratio in African populations

Abstract

Objective: Understanding the genetic underpinnings of anthropometric traits in diverse populations is crucial for gaining insights into their biological mechanisms and potential implications for health.

Methods: We conducted a genome-wide association study, meta-analysis, and gene set analysis of waist-hip ratio (WHR), WHR adjusted for BMI (WHRadjBMI), waist circumference, BMI, and height using the African Collaborative Center for Microbiome and Genomics Research (ACCME) cohort (n = ~11,000) for discovery and polygenic score target analyses and the Africa America Diabetes Mellitus (AADM) study (n = ~5200) for replication and polygenic score validation. We generated and compared polygenic scores from European, African, Afro-Caribbean, and multiethnic ancestry populations.

Results: The top loci associated with each trait in the meta-analysis were in CD36 (rs3211826 [p = 5.90 × 10^-12] for WHR and rs73709003 [p = 1.75 × 10^-13] for WHRadjBMI), IFI27L1 (rs59775050 [p = 2.66 × 10^-08] for waist circumference), INPP4B (rs2636629 [p = 1.44 × 10^-09] for BMI), and HMGA1 (rs6937622 [p = 1.40 × 10^-15] for height) gene regions. A novel variant rs7797157, near GNAT3, was also significantly associated with WHR (p = 2.50 × 10^-10) and WHRadjBMI (p = 2.66 × 10^-11). The ancestry-specific parameters for the best predictive polygenic scores were European ancestry (R² = 0.68%; p = 1.63 × 10^-16) and multiethnic ancestry (R² = 0.06%; p = 1.29 × 10^-02) for WHR; European ancestry (R² = 1.36%; p = 2.94 × 10^-31) and multiethnic ancestry (R² = 1.12%; p = 3.52 × 10^-25) for BMI; and European ancestry (R² = 3.16%; p = 2.95 × 10^-73), African ancestry (R² = 4.16%; p = 1.75 × 10^-96), and African and Afro-Caribbean ancestry (R² = 2.67%; p = 4.35 × 10^-62) for height.

Conclusions: The discovery of a novel locus for WHR and genetic signals for each trait and the assessment of polygenic score performance underscore the importance of conducting well-powered studies in diverse populations.