Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis.

BACKGROUND: The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear. METHODS: By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders. RESULTS: SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07­1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06­1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04­1.18, p = 1.84 × 10−3). CONCLUSIONS: We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

Genetic evidence for the causal impact of insomnia on gastrointestinal diseases and the mediating effects of adiposity traits.

BACKGROUND AND AIM: Insomnia has been implicated in gastrointestinal diseases (GIs), but the causal effect between insomnia and GIs and underlying mechanisms remain unknown. METHODS: By using the released summary-level data, we conducted a two-step Mendelian randomization (MR) analysis to examine the relationship between insomnia and four GIs and estimate the mediating role of candidate mediators. The first step was to investigate the causal association between insomnia and GIs using univariable MR analysis. The second step was to estimate the mediation proportion of selected mediators in these associations using multivariable MR analysis. Subsequently, results from different datasets were combined using the fixed-effect meta-analysis. RESULTS: Univariable MR analysis provided strong evidence for the causal effects of insomnia on four GIs after Bonferroni correction for multiple comparisons, including peptic ulcer disease (PUD) (odds ratio [OR] = 1.15, 95% interval confidence [CI] = 1.10-1.20, P = 1.83 × 10-9), gastroesophageal reflux (GORD) (OR = 1.19, 95% CI = 1.16-1.22, P = 5.95 × 10-42), irritable bowel syndrome (IBS) (OR = 1.18, 95% CI = 1.15-1.22, P = 8.69 × 10-25), and inflammatory bowel disease (IBD) (OR = 1.09, 95% CI = 1.03-1.05, P = 3.46 × 10-3). In the mediation analysis, body mass index (BMI) and waist-to-hip ratio (WHR) were selected as mediators in the association between insomnia and PUD (BMI: mediation proportion [95% CI]: 13.61% [7.64%-20.70%]; WHR: 8.74% [5.50%-12.44%]) and GORD (BMI: 11.82% [5.94%-18.74%]; WHR: 7.68% [4.73%-11.12%]). CONCLUSIONS: Our findings suggest that genetically instrumented insomnia has causal effects on PUD, GORD, IBS, and IBD, respectively. Adiposity traits partially mediated the associations between insomnia and GIs. Further clinical studies are warranted to evaluate the protective effect of insomnia treatment on GIs.

Genetic Links Between Metabolic Syndrome and Osteoarthritis: Insights from Cross-Trait Analysis.

BACKGROUND: Previous observational studies have indicated a bidirectional association between metabolic syndrome (MetS) and osteoarthritis (OA). However, it remains unclear whether these bidirectional associations reflect causal relationships or shared genetic factors, and the underlying biological mechanisms of this association are not fully understood. METHODS: Leveraging summary statistics from genome-wide association studies (GWASs) conducted by the UK Biobank and the Glucose and Insulin-related Traits Consortium (MAGIC), we performed global genetic correlation analyses, genome-wide cross-trait meta-analyses, and a bidirectional two-sample Mendelian randomization analyses using summary statistics from GWASs to comprehensively assess the relationship of MetS and OA. RESULTS: We first detected an extensive genetic correlation between MetS and OA (rg=0.393, P=1.52×10-18), which was consistent in four MetS components, including waist circumference, triglycerides, hypertension and high-density lipoprotein cholesterol and OA with rg ranging from -0.229 to 0.490. We then discovered 32 variants jointly associated with MetS and OA through multi-trait Analysis of GWAS. Co-localization analysis founded 12 genes shared between MetS and OA, with functional implications in several biological pathways. Finally, MR analysis suggested genetic liability to MetS significantly increased the risk of OA, but no reverse causality was found. CONCLUSION: Our results illustrate a common genetic architecture, pleiotropic loci, as well as causality between MetS and OA, potentially enhancing our knowledge of high comorbidity and genetic processes that overlap between the two disorders.