Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies.
Böhmer AC., Hecker J., Schröder J., Gharahkhani P., May A., Gerges C., Anders M., Becker J., Hess T., Kreuser N., Thieme R., Noder T., Venerito M., Veits L., Schmidt T., Fuchs C., Izbicki JR., Hölscher AH., Dietrich A., Moulla Y., Lyros O., Lang H., Lorenz D., Schumacher B., Mayershofer R., Vashist Y., Ott K., Vieth M., Weismüller J., Moebus S., Knapp M., Neuhaus H., Rösch T., Ell C., Nöthen MM., Whiteman DC., Tomlinson I., Jankowski J., Fitzgerald RC., Palles C., Vaughan TL., Gockel I., Thrift AP., Fier H., Schumacher J.
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 (rg = 0.13, P = 2 × 10-04) and a rg 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 (rg = 0.17, P = 1.2 × 10-03), and WHR and EA in males (rg = 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.