Shared genetic architecture of obesity and gastroesophageal reflux disease

Obesity is identified as a risk factor of gastroesophageal reflux disease (GERD). This study aims to elucidate the shared genetic architecture of obesity-related phenotypes and GERD. Based on the publicly available genome-wide association studies’ datasets, this genome-wide pleiotropic association study was conducted with various genetic approaches (including linkage disequilibrium score regression, high-definition likelihood inference for genetic correlations, pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis) sequentially to unravel the genetic associations from single-nucleotide polymorphism to gene levels, and to reveal the underlying shared genetic architecture between obesity-related phenotypes and GERD. This study discovered shared genetic mechanisms between GERD and several obesity-related phenotypes, including arm fat percentage (left), arm fat percentage (right), leg fat percentage (left), leg fat percentage (right), trunk fat percentage, waist-to-hip ratio, and body mass index. Significant genetic correlations were observed by linkage disequilibrium score regression and high-definition likelihood inference for genetic correlations, with multiple associated pleiotropic loci and their mapped genes identified by pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis. Additionally, several brain tissues were identified to be linked to both obesity and GERD by multi-marker analysis of genomic annotation. This research provided strong evidence of genetic correlations and brought novel insights into the underlying genetic connections and shared genetic architectures of obesity and GERD.