Abstract

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, 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 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.

Authors	Böhmer, Anne Christin; Hecker, Julian; Schröder, Julia; Gharahkhani, Puya; May, Andrea; Gerges, Christian; Anders, Mario; Becker, Jessica; Hess, Timo; Kreuser, Nicole; Thieme, Rene; Noder, Tania; Venerito, Marino; Veits, Lothar; Schmidt, Thomas; Fuchs, Claudia; Izbicki, Jakob R; Hölscher, Arnulf H; Dietrich, Arne; Moulla, Yusef; Lyros, Orestis; Lang, Hauke; Lorenz, Dietmar; Schumacher, Brigitte; Meyershofer, Rupert; Vashist, Yogesh K; Ott, Katja; Vieth, Michael; Weissmüller, Josef; Moebus, Susanne; Knapp, Michael; Neuhaus, Horst; Rösch, Thomas; Ell, Christian; Nöthen, Markus M; Whiteman, David C; Tomlinson, Ian; Jankowski, Janusz A; Fitzgerald, Rebecca C; Palles, Claire; Vaughan, Thomas L; Gockel, Ines; Thrift, Aaron P; Fier, Heide; Schumacher, Johannes
Journal	Cancer Epidemiology Biomarkers and Prevention
Pages	427-433
Volume	29
Date	1/11/2019
Grant ID	O-149.0121
Funding Body	BONFOR-program of the Medical Faculty, University of Bonn
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1158/1055-9965.EPI-19-0374