Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights From Genome-Wide Association Studies
Anne C Böhmer # 1 2 , Julian Hecker # 3 , Julia Schröder 4 2 , Puya Gharahkhani 5 , Andrea May 6 , Christian Gerges 7 , Mario Anders 8 9 , Jessica Becker 4 2 , Timo Hess 10 , Nicole Kreuser 11 , René Thieme 11 , Tania Noder 8 , Marino Venerito 12 , Lothar Veits 13 , Thomas Schmidt 14 , Claudia Fuchs 15 , Jakob R Izbicki 16 , Arnulf H Hölscher 15 , Arne Dietrich 11 , Yusef Moulla 11 , Orestis Lyros 11 , Hauke Lang 17 , Dietmar Lorenz 18 , Brigitte Schumacher 19 , Rupert Mayershofer 20 , Yogesh Vashist 16 21 , Katja Ott 14 22 , Michael Vieth 13 , Josef Weismüller 23 , Susanne Moebus 24 , Michael Knapp 25 , Horst Neuhaus 7 , Thomas Rösch 8 , Christian Ell 6 , Markus M Nöthen 4 2 , David C Whiteman 26 , Ian Tomlinson 27 , Janusz Jankowski 28 29 , Rebecca C Fitzgerald 30 , Claire Palles 27 , Thomas L Vaughan 31 , Ines Gockel 11 , Aaron P Thrift 32 33 , Heide Fier # 3 , Johannes Schumacher # 4 10
PMID: 31748258 DOI: 10.1158/1055-9965.EPI-19-0374
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.
©2019 American Association for Cancer Research.