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 metaanalyses 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 x 10(-04)) and a r(g) of 0.12 between WHR and BE/EA (P = 1 x 10(-02)). Sexspecific analyses revealed a pronounced genetic correlation between BMI and EA in females (r(g) = 0.17, P = 1.2 x 10(-03)), and WHR and EA in males (r(g) = 0.18, P = 1.51 x 10(-02)). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 x 10(-03)) and WHR and BE/EA risk variants (P = 2 x 10(-02)). Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mechanisms. 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.