Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease

Yuanlin Sun; Xueyuan Cao; Donghui Cao; Yingnan Cui; Kaisheng Su; Zhifang Jia; Yanhua Wu; Jing Jiang

doi:10.3389/fnut.2022.1009122

Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease

Front Nutr. 2022 Nov 1:9:1009122. doi: 10.3389/fnut.2022.1009122. eCollection 2022.

Authors

Yuanlin Sun¹, Xueyuan Cao¹, Donghui Cao², Yingnan Cui¹, Kaisheng Su², Zhifang Jia², Yanhua Wu², Jing Jiang²

Affiliations

¹ Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China.
² Department of Clinical Epidemiology, The First Hospital of Jilin University, Changchun, Jilin, China.

Abstract

Background: Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal dysfunction that significantly affects the quality of daily life, and health interventions are challenging to prevent the risk of GORD. In this study, we used Mendelian randomization framework to genetically determine the causal associations between multifaceted modifiable factors and the risk of GORD.

Materials and methods: Sixty-six exposures with available instrumental variables (IVs) across 6 modifiable pathways were included in the univariable MR analysis (UVMR). Summary-level genome-wide association studies (GWAS) datasets for GORD were retrieved from the Neale Lab (GORD _Neale , Ncases = 29975, Ncontrols = 390556) and FinnGen (GORD _Finn , Ncases = 13141, Ncontrols = 89695). Using the METAL software, meta-analysis for single nucleotide polymorphisms (SNPs) from GORD _Neale and GORD _Finn was conducted with an inverse variance weighted (IVW) fixed-effect model. Moreover, we leveraged partition around medoids (PAM) clustering algorithm to cluster genetic correlation subtypes, whose hub exposures were conditioned for multivariable MR (MVMR) analyses. P-values were adjusted with Bonferroni multiple comparisons.

Results: Significant causal associations were identified between 26 exposures (15 risk exposures and 11 protective exposures) and the risk of GORD. Among them, 13 risk exposures [lifetime smoking, cigarette consumption, insomnia, short sleep, leisure sedentary behavior (TV watching), body mass index (BMI), body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, major depressive disorder, and anxious feeling], and 10 protective exposures (leisure sedentary behavior (computer use), sitting height, hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence) showed novel significant causal associations with the risk of GORD. Moreover, 13 exposures still demonstrated independent associations with the risk of GORD following MVMR analyses conditioned for hub exposures (educational attainment, smoking initiation and BMI). In addition, 12 exposures showed suggestive causal associations with the risk of GORD.

Conclusion: This study systematically elucidated the modifiable factors causally associated with the risk of GORD from multifaceted perspectives, which provided implications for prevention and treatment of GORD.

Keywords: Mendelian randomization; discovery phase; gastro-oesophageal reflux disease; meta-analysis; modifiable factors; replication phase.