Causal effects of genetic birth weight and gestational age on adult esophageal diseases: Mendelian randomization study

Figure 1 Flowchart of Mendelian randomization analyses in this study. Step 1: The causal effects of gestational duration, gestational age, and birth weight on gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), esophageal adenocarcinoma (EA); Step 2: The causal effects of birth weight on eight risk factors; Step 3: The causal effects of eight risk factors on GERD, BE, EA; Step 4: The causal effects of eight risk factors on GERD, BE, EA after adjusting birth weight. BE: Barrett’s esophagus; EA: Esophageal adenocarcinoma; EGG: Early Growth Genetics; GWAS: Genome-wide association study; IVs: Instrumental variables; IVW: Inverse variance weighted; MR-PRESSO: MR-Pleiotropy RESidual sum and outlier; UVMR: Univariable Mendelian randomization; SNPs: Single nucleotide polymorphisms; GERD: Gastroesophageal reflux disease; MVMR: Multivariable Mendelian randomization; LD: Linkage disequilibrium.

Figure 2 Univariable Mendelian randomization analysis. A: Univariable Mendelian randomization analysis of gestational age-related genetic characteristics, birth weight and causality of esophageal disease; B: Univariable Mendelian randomization analysis of causal effects of genetic birth weight on risk factors. ^aP < 0.05. BE: Barrett’s esophagus; CI: Confidence interval; EA: Esophageal adenocarcinoma; GERD: Gastroesophageal reflux disease; nSNPs: Number of single nucleotide polymorphisms; OR: Odds ratio.

Figure 3 Multivariable Mendelian randomization analysis of causal effects of risk factors on esophageal disease after adjusting for birth weight. ^aP < 0.05. Helicobacter pylori phenotypes do not acquire sufficient single nucleotide polymorphisms in multivariable Mendelian randomization. GERD: Gastroesophageal reflux disease; BE: Barrett’s esophagus; EA: Esophageal adenocarcinoma; OR: Odds ratio; CI: Confidence interval; nSNPs: Number of single nucleotide polymorphisms.

Figure 4 Combined effects of multiple mediators on esophageal diseases. The combined proportions mediated by educational attainment and height for the effect of birth weight on Barrett’s esophagus. βa: The effect of birth weight on the risk of modifiable risk factors; βb: The effect of risk factors on the risk of Barrett’s esophagus after combination of mediating factors; Total effect: The effect of birth weight on the risk of Barrett’s esophagus; BE: Barrett’s esophagus.