Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits.

Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses.

Results: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (r_g = 0.13, P = 2 × 10⁻⁰⁴) and a r_g of 0.12 between WHR and BE/EA (P = 1 × 10⁻⁰²). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (r_g = 0.17, P = 1.2 × 10⁻⁰³), and WHR and EA in males (r_g = 0.18, P = 1.51 × 10⁻⁰²). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 × 10⁻⁰³) and WHR and BE/EA risk variants (P = 2 × 10⁻⁰²).

Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mecha-nisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA.

Impact: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.