Background: Major depressive disorder (MDD) is clinically documented to co-occur with multiple gastrointestinal disorders (GID), but the potential causal relationship between them remains unclear. We aimed to evaluate the potential causal relationship of MDD with 4 GID [gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), peptic ulcer disease (PUD), and non-alcoholic fatty liver disease (NAFLD)] using a two-sample Mendelian randomization (MR) design.Methods: We obtained genome-wide association data for MDD from a meta-analysis (N = 480 359), and for GID from the UK Biobank (N ranges: 332 601–486 601) and FinnGen (N ranges: 187 028–218 792) among individuals of European ancestry. Our primary method was inverse-variance weighted (IVW) MR, with a series of sensitivity analyses to test the hypothesis of MR. Individual study estimates were pooled using fixed-effect meta-analysis.Results: Meta-analyses IVW MR found evidence that genetically predicted MDD may increase the risk of GERD, IBS, PUD and NAFLD. Additionally, reverse MR found evidence of genetically predicted GERD or IBS may increase the risk of MDD.Conclusions: Genetically predicted MDD may increase the risk of GERD, IBS, PUD and NAFLD. Genetically predicted GERD or IBS may increase the risk of MDD. The findings may help elucidate the mechanisms underlying the co-morbidity of MDD and GID. Focusing on GID symptoms in patients with MDD and emotional problems in patients with GID is important for the clinical management.

BACKGROUND: The impact of pain intensity on the progression trajectories of cardiometabolic multimorbidity (CMM) is not well understood. We attempted to dissect the relationship of short-term pain (STP) and chronic pain intensity with the temporal progression of CMM. METHODS: We conducted a prospective cohort study based on the UK Biobank participants. Incident cases of cardiometabolic diseases (CMDs) were identified based on self-reported information and multiple health-related records in the UK Biobank. CMM was defined as the occurrence of at least 2 CMDs, including heart failure (HF), ischemic heart disease (IHD), stroke, and type 2 diabetes (T2D). The pain intensity was categorized into 5 levels based on pain duration and the number of sites involved, including chronic widespread pain (CWSP), chronic multilocation pain (CMLP), chronic single-location pain (CSLP), STP, and free-of-pain (FOP). Multistate models were used to assess the impact of pain intensity on the CMM trajectories from enrollment to initial cardiometabolic disease (ICMD), subsequently to CMM, and ultimately to death. RESULTS: A total of 429,145 participants were included. Over the course of a 12.8-year median follow-up, 13.1% (56,137/429,145) developed ICMD, 19.6% (10,979/56,137) further progressed to CMM, and a total of 5.3% (22,775/429,145) died. Compared with FOP, CMLP (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.06–1.17) and CWSP (HR, 1.26; 95% CI, 1.13–1.42) elevated the risk of transitioning from ICMD to CMM. STP (HR, 0.89; 95% CI, 0.82–0.96), CSLP (HR, 0.88; 95% CI, 0.82–0.95), and CMLP (HR, 0.87; 95% CI, 0.81–0.93) lowered the risk of transition from ICMD to mortality, and STP also reduced the risk of transition from enrollment to mortality (HR, 0.94; 95% CI, 0.89–0.98). The results of disease-specific transitions revealed that the influence of pain intensity varied across transitional stages. Specifically, CMLP and CWSP heightened the risk of conversion from T2D or IHD to CMM, whereas only CWSP substantially elevated the transition risk from HF to CMM. CONCLUSIONS: Our results highlighted reductions in chronic pain may mitigate both the onset and progression of CMM, potentially having an important impact on future revisions of cardiometabolic and pain-related guidelines.

Background: Empirical studies have demonstrated that educational attainment (EA) is associated with neuropsychiatric disorders (NPDs), suggesting a shared etiological basis between them. However, little is known about the shared genetic mechanisms and causality behind such associations.Methods: This study explored the shared genetic basis and causal relationships between EA and NPDs using the high-definition likelihood (HDL) method, cross phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) with summary-level data for EA (N = 293,723) and NPDs (N range = 9,725 to 455,258).Results: Significant genetic correlations between EA and 12 NPDs (r_g range − 0.49 to 0.35; all p < 3.85 × 10⁻³) were observed. CPASSOC identified 37 independent loci shared between EA and NPDs, one of which was novel (rs71351952, mapped gene: ARFGEF2). Functional analyses and TWAS found shared genes were enriched in brain tissue, especially in the cerebellum and highlighted the regulatory role of neuronal signaling, purine nucleotide metabolic process, and cAMP-mediated signaling pathways. CPASSOC and TWAS supported the role of three regions of 6q16.1, 3p21.31, and 17q21.31 might account for the shared causes between EA and NPDs. MR confirmed higher genetically predicted EA lower the risk of ADHD (OR_IVW: 0.50; 95% CI: 0.39 to 0.63) and genetically predicted ADHD decreased the risk of EA (Causal effect: −2.8 months; 95% CI: −3.9 to −1.8).Conclusion: These findings provided evidence of shared genetics and causation between EA and NPDs, advanced our understanding of EA, and implicated potential biological pathways that might underlie both EA and NPDs.

Background: Nonalcoholic fatty liver disease (NAFLD) was clinically documented to be accompanied by iron homeostasis imbalances, however, the causal relationship between them remains unclear. Therefore, this study aimed to examine the relationship between iron homeostasis indicators (serum iron, ferritin, transferrin, total iron binding capacity (TIBC), and transferrin saturation (TSAT)) and NAFLD risk. Methods: We applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to iron homeostasis indicators (N = 43,220–246,139) on NAFLD risk (N = 377,988) in individuals of European ancestry. Reverse direction MR, multivariable MR, and two-step MR were performed to estimate reverse association, causal effects independent of smoking or drinking, and the mediating effect of lipid metabolism, respectively. Smoking and drinking as confounders were considered confounders. Results: Genetically predicted serum iron, ferritin, and TSAT were significantly associated with a higher risk of NAFLD (odds ratio (OR): 1.286, 95% confidence interval (CI): 1.075–1.539; p = 0.0059; OR: 1.260, 95% CI: 1.050–1.500, p = 0.0195; and OR: 1.223, 95% CI: 1.067–1.402; p = 0.0039, respectively). Reverse direction MR analysis suggested that genetic liability to NAFLD had no significant causal effect on iron homeostasis. Sex-specific MR exhibited a stronger effect size for the association of elevated ferritin with NAFLD risk in males (OR: 1.723, 95% CI: 1.338–2.219; p = 2.48 × 10-5). Two-step MR revealed that elevated triglycerides (TGs) mediated approximately 3%–5% of the observed effect of serum iron and TSAT on NAFLD risk, while decreased low-density lipoprotein cholesterol (LDL-C) mediated 9%–10%. Conclusion: Genetic liability to iron status imbalance may causally affect NAFLD. This evidence may support the clinical treatment of NAFLD in the target population.