Depression Promotes Gastroesophageal Reflux Disease: New Evidence Based on Mendelian Randomization.

BACKGROUND: Although observational studies have reported that depression is a risk factor for gastroesophageal reflux disease, it is difficult to determine the potential causal correlation. Thus, this study investigated the causal relevance of depression for gastroesophageal reflux disease using Mendelian randomization and provided new evidence for their association. METHODS: Based on data from the UK Biobank, we assessed the causality of the 2 diseases by analyzing 135 458 severe depressive disorder cases and 41 024 gastroesophageal reflux disease cases. The causal inference was assessed using inverse-variance weighting, weighted median, Mendelian randomization-Egger, and weighted median methods. Simultaneously, pleiotropy and sensitivity analyses were used for quality control. Finally, we also explored whether depression affects gastroesophageal reflux disease through other risk factors. RESULTS: A positive causal relationship between depression and gastroesophageal reflux disease was found in the inverse-variance weighted and weighted median methods, both of which were statistically significant [odds ratio = 1.011, 95% CI: 1.004-1.017, P =.001; odds ratio = 1.011, 95% CI: 1.004-1.020, P =.002)]. Sensitivity analyses were consistent with a causal interpretation, and the main deviation of genetic pleiotropy was not found (Intercept ß = 0.0005; SE = 0.005, P =.908). The genetic susceptibility to depression was also associated with smoking, insomnia, and sleep apnea (odds ratio = 1.166, 95% CI: 1.033-1.316, P =.013; odds ratio = 1.089, 95% CI: 1.045-1.134; and odds ratio = 1.004, 95% CI: 1.001-1.006, P =.001, respectively). CONCLUSION: Our results verified a causal correlation that depression could slightly increase the risk of gastroesophageal reflux disease.

Childhood asthma and type 1 diabetes mellitus: A meta-analysis and bidirectional Mendelian randomization study.

BACKGROUND: Worldwide incidence and prevalence of both asthma and type 1 diabetes mellitus (T1DM) in children have been increasing in past decades. Association between the two diseases has been found in some but not in other studies. OBJECTIVE: We conducted a meta-analysis to verify such an association, and bidirectional Mendelian randomization analysis to examine the potential cause-effect relationships. METHODS: Three databases (PubMed, Embase, and Web of Science) were searched from their inception to February 1, 2021. Pooled hazard ratios (HR) or odds ratios (OR), and 95% confidence intervals, were calculated. Associations between single-nucleotide polymorphisms with childhood asthma and T1DM were selected based on genome-wide association studies. The outcome datasets were obtained from FinnGen study. We used the inverse-variance-weighted (IVW), weighted median and MR-Egger methods to estimate causal effects. To assess robustness and horizontal pleiotropy, MR-Egger regression and MR pleiotropy residual sum and outlier test were conducted. RESULTS: In meta-analysis, childhood asthma was associated with an increased risk of T1DM (HR = 1.30, 95% CI 1.05-1.61, P = .014), whereas T1DM was not associated with the risk of asthma (HR = 0.98, 95% CI 0.64-1.51, P = .941; OR = 0.84, 95% CI 0.65-1.08, P = .168). MR analysis indicated increased genetic risk of T1DM in children with asthma (OR = 1.308; 95% CI 1.030-1.661; P = .028). Analysis using the IVW method indicated no association between T1DM and genetic risk of asthma (OR = 1.027, 95%CI 0.970-1.089, P = .358). CONCLUSION: Both meta-analysis and MR study suggested that childhood asthma was a risk factor for T1DM. No epidemiological or genetic evidence was found for an association of T1DM with asthma incidence. Further studies could be carried out to leverage this newfound insight into better clinical and experimental research in asthma and T1DM.

Causal Association between Whole-Body Water Mass and Sleep Apnea: A Mendelian Randomization Study.

Rationale: Growing evidence has suggested that body water content plays a critical role in sleep apnea. However, the causal relationship has not been established. Objectives: This study aimed to investigate whether increased whole-body water mass is causally associated with a higher risk of sleep apnea using two-sample Mendelian randomization (MR) analysis. Methods: Body water mass (BWM)-associated genetic instruments were extracted from a genome-wide association study conducted by Neale Lab, which incorporates 331,315 individuals of European ancestry. Genetic variants for sleep apnea were derived from the FinnGen dataset. MR analysis was performed using inverse variance-weighted and weight median methods, respectively. MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier tests were applied to evaluate the directional pleiotropy. In addition, we performed a multivariable MR analysis that includes body mass index, snoring, and waist-to-hip ratio as covariate exposures to address their confounding effects. To elucidate mechanisms of the association between BWM and sleep apnea, we further conducted MR analysis on common edematous diseases. Results: MR estimates showed that per standard deviation increase in BWM led to an increase in the risk of sleep apnea by 49% (odds ratio [OR], 1.490; 95% confidence interval [CI], 1.308-1.696; P = 1.75 × 10-9). The result after MR-Pleiotropy Residual Sum and Outlier correction further supports their causal association (OR, 1.414; 95% CI, 1.253-1.595; P = 1.76 × 10-8). In addition, the multivariable MR analysis indicates a significant causal association between a higher BWM and increased risk of sleep apnea (OR, 1.204; 95% CI, 1.031-1.377; P = 0.036). Genetic predisposition to a higher BWM was also causally related to increased risk of edematous diseases. Conclusions: Our results suggested that increased BWM is a potential risk factor for sleep apnea. Pathologic edema is a possible intermediate factor mediating this causal association.

Educational attainment could be a protective factor against obstructive sleep apnea: a study based on Mendelian randomization.

BACKGROUND: Causality between education and obstructive sleep apnea (OSA) is not known. METHODS: Genetic variants, as instrumental variables for years of education, were derived from the Social Science Genetic Association Consortium. The outcome datasets related to OSA were from the FinnGen research project (www.finngen.fi/en/). Inverse variance-weighted, weighted-median, and Mendelian randomization-Egger analysis were used to estimate causal effects. To assess the robustness and horizontal pleiotropy of significant results, leave-one-out sensitivity analysis and Mendelian randomization-Egger regression analysis were conducted. The inverse variance-weighted method was undertaken to estimate the association between years of education and other known risk factors for OSA. Analyses were conducted using the Two Sample Mendelian Randomization package of R 4·0·3. RESULTS: Genetic predisposition towards 4.2 years of additional education was associated with a 27.8% lower risk of OSA [odds ratio (OR) =0.722, 95% confidence interval (CI): 0.566-0.921; P=0.009]. Sensitivity analyses were consistent with a causal interpretation in which a major bias from genetic pleiotropy was unlikely. The Mendelian randomization assumptions did not seem to be violated. Genetic predisposition towards longer education was associated with a lower body mass index, fewer cigarettes smoked per day, and greater alcohol intake per week. CONCLUSIONS: Our data indicated that education could be a protective factor against OSA. Potential mechanisms could include body mass index, tobacco smoking, and alcohol intake.