Shared genetic architecture between major depressive disorder and inflammatory bowel disease: Insights from large-scale genome-wide cross-trait analysis.

Patients with schizophrenia (SCZ) frequently present with comorbid gastrointestinal diseases. However, the cross-disorder genetic correlations and shared mechanisms remain largely unknown. This study aims to elucidate the shared genetic architecture between SCZ and five types of gastrointestinal diseases: inflammatory bowel disease, Crohn's disease, ulcerative colitis, constipation, and irritable bowel syndrome. Furthermore, we seek to identify shared genetic risk loci, pinpoint potentially implicated tissues, and conduct in-depth analyses of the genetic mechanisms. Using summary statistics from large-scale genome-wide association studies (GWAS), we conducted an in-depth analysis of the genetic correlations between schizophrenia (SCZ) and gastrointestinal diseases via linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods. Significant genetic correlations were observed between SCZ and gastrointestinal diseases. To further investigate the shared genetic basis, we performed cross-trait pleiotropy analyses to identify common pleiotropic loci and genes. Additionally, to uncover potential links between these complex traits, we conducted comprehensive functional annotation and tissue-specific enrichment analyses. Heritability enrichment analysis was employed to assess the contributions of key tissues. Finally, immune colocalization approaches were utilized to explore immune-mediated relationships between SCZ and gastrointestinal diseases. Our research highlighted shared genetic mechanisms between SCZ and five gastrointestinal diseases. A total of 2,367 novel SNPs were identified at a genome-wide significance level (P < 5 × 10⁻⁸), and annotation revealed 96 pleiotropic genome-wide risk loci, among which 32 passed causal colocalization analysis. Shared loci were identified at regions 1q32.1, 2q33.1, 3p21.31, 10q21.2, 16p11.2, and 18q21.2. Further gene-level analyses identified pleiotropic genes including C1orf106, SLC26A6, FES, BSN, C3orf62 and CELSR3. Pathway analyses revealed critical roles of FOXP3 target genes, lymphocyte activation, T cell activation, and PDZ domain-related pathways in these diseases. Finally, phenotype-level immune colocalization analysis uncovered immunological mediators including PD-L1, CD3, T cells, and CD28 that bridge SCZ and gastrointestinal diseases. Our findings support a shared genetic architecture between SCZ and gastrointestinal diseases and shed light on the potential mechanism that might involve in.These findings hold important implications for coordinated interventions targeting SCZ and its comorbid conditions.

Genetic correlation, pleiotropic loci and shared risk genes between major depressive disorder and gastrointestinal tract disorders.

The aim of this study was to explore the shared genetic architecture between inflammatory bowel disease and depression and other upper gastrointestinal dysfunctions and inflammatory diseases, and to identify shared risk loci, potential key tissues, and associated genetic mechanisms to study. Based on pooled data from a large-scale genome-wide association study (GWAS), we observed a genetic correlation between inflammatory bowel disease and depression and other upper gastrointestinal tract dysfunctions and inflammatory disorders and performed cross-trait pleiotropy analyses to detect shared pleiotropic loci and genes. In addition, we performed a series of functional annotation and tissue-specific analyses to determine the impact of pleiotropic genes. Genetic power enrichment analysis was used to detect key immune cells and tissues. Finally, immunological associations between these diseases were explored using an immunolocalization approach. Our study highlights the existence of shared genetic mechanisms between depression, IBS, GORD, chronic gastritis, and IBD. A total of 160 promising pleiotropic loci were identified at the genome-wide significance level (P: 5 × 10-8) and annotation identified 54 dominant risk SNP loci, 30 of which passed causal co-localization tests. Further gene level analyses identified 2 unique pleiotropic genes such as rs142762983 and rs7865719. Pathway analyses identified nikolsky breast cancer 17q11 q21 amplicon, kegg type idiabetes mellitus, and gg intestinal immune network for iga production. The key role of these signaling pathways in these disorders was demonstrated by SNP level and gene level tissue enrichment analyses, which showed that pleiotropic mechanisms were significantly enriched in WholB blood, Spleen, Colon Transverse, and Small Intestine Terminal Ileum. Final analysis of immune cells byphenotypic levelimmunolocalization results showed 49 pleiotropic loci that support an important role for five unique immune cells in IBD and depression and three other gastrointestinal disorders through shared causal variants. Our study demonstrates the existence of a genetic association between symptomatic bowel disease and depression and other upper gastrointestinal tract dysfunctions and inflammatory disorders and reveals underlying immunomodulatory mechanisms.

Improved understanding of the shared genetic architecture between psychiatric disorders and brain white matter may provide mechanistic insights for observed phenotypic associations. Our objective is to characterize the shared genetic architecture of bipolar disorder (BD), major depression (MD), and schizophrenia (SZ) with white matter fractional anisotropy (FA) and identify shared genetic loci to uncover biological underpinnings. We used genome-wide association study (GWAS) summary statistics for BD (n = 413,466), MD (n = 420,359), SZ (n = 320,404), and white matter FA (n = 33,292) to uncover the genetic architecture (i.e., polygenicity and discoverability) of each phenotype and their genetic overlap (i.e., genetic correlations, overlapping trait-influencing variants, and shared loci). This revealed that BD, MD, and SZ are at least 7-times more polygenic and less genetically discoverable than average FA. Even in the presence of weak genetic correlations (range = -0.05 to -0.09), average FA shared an estimated 42.5%, 43.0%, and 90.7% of trait-influencing variants as well as 12, 4, and 28 shared loci with BD, MD, and SZ, respectively. Shared variants were mapped to genes and tested for enrichment among gene-sets which implicated neurodevelopmental expression, neural cell types, myelin, and cell adhesion molecules. For BD and SZ, case vs control tract-level differences in FA associated with genetic correlations between those same tracts and the respective disorder (rBD = 0.83, p = 4.99e-7 and rSZ = 0.65, p = 5.79e-4). Genetic overlap at the tract-level was consistent with average FA results. Overall, these findings suggest a genetic basis for the involvement of brain white matter aberrations in the pathophysiology of psychiatric disorders.

BackgroundComorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, but the underlying intrinsic link between Alzheimer’s disease (AD) and inflammatory bowel disease (IBD) is not adequately understood.MethodsTo identify pathogenic cell types of AD and IBD and explore their shared genetic architecture, we developed Pathogenic Cell types and shared Genetic Loci (PCGL) framework, which studied AD and IBD and its two subtypes of ulcerative colitis (UC) and Crohn’s disease (CD).ResultsWe found that monocytes and CD8 T cells were the enriched pathogenic cell types of AD and IBDs, respectively. By PCGL framework, there was a significant global genetic correlation between AD and each of IBD, UC, and CD. Especially, local genetic correlations between AD and IBD showed strong signals in chr6. Bidirectional two-sample MR Analyses also validated these. Cross-trait meta-analysis identified two key genetic loci rs660895 (on chr6) and rs917117 (on chr7), which have not been previously reported. Two loci are located on the genes HLA-DRB1 and JAZF1, respectively. MAGMA genome-wide gene-based analysis identified six overlapping genes including HLA-DRB1. Subsequently, for one thing, SMR analyses further validated six shared genes in specific tissues and monocytes. For another, pathway enrichment analysis revealed shared genes were enriched in several natural killer cell mediated cytotoxicity and chemokine signaling pathways.ConclusionsPCGL not only revealed the significant genetic correlations underlying AD and IBDs but also identified enriched pathogenic cell types and new shared loci and genes. We highlighted the mediation of HLA-DRB1 effects in the comorbidity mechanisms.

The occurrence of ischemic heart disease (IHD), atrial fibrillation, and flutter demonstrates certain associations with inflammatory bowel disease (IBD), warranting further exploration at the genetic architecture level. This study focused on genome-wide association study (GWAS) data of IHD, atrial fibrillation and flutter, and IBD, analyzing from two dimensions: genetic correlation and shared locus identification. Initially, linkage disequilibrium score regression and genetic covariance analyzer were utilized to assess the overall genetic correlations. Subsequently, the association patterns of local genomic regions were determined using Local Ancestry Variance Association (LAVA) analysis. Mendelian randomization (MR) was employed to assess causal effects. The genetic overlap among different traits was analyzed based on the statistical framework of conditional/conjunctional false discovery rate (cond/conjFDR). Finally, shared loci across these traits were identified by integrating conjFDR analysis with GWAS multi-trait analysis (MTAG). At the genomic level, significant overall correlations were observed among IHD, atrial fibrillation and flutter, and IBD and Crohn's disease (CD), while associations with ulcerative colitis appeared less pronounced. At the local level, IHD and IBD (including subtypes) showed significant associations in multiple regions. However, atrial fibrillation and flutter exhibited local associations only in the context of CD. Through conjFDR analysis, the genetic overlap across these diseases was validated. Additionally, several shared genetic loci were identified by integrating conjFDR and MTAG analyses, with genes confirmed in both IHD and IBD (including subtypes), such as SMAD3, PLCG2, ZNF831, PTPN22, RP11-136O12.2, and RP11-449I17.5. Moreover, six common genes were identified in the analysis between atrial fibrillation and flutter and IBD (including subtypes), such as ZMIZ1, MTHFS, ERAP2, GNA12, and RP1-15D23.2. This study offers empirical evidence of the genetic association between IHD, atrial fibrillation and flutter, and IBD comorbidity, providing new insights for cases where IBD co-occurs with IHD or atrial fibrillation and flutter.

Background Inflammatory bowel disease (IBD) is a chronic, inflammatory, and autoimmune disorder[1], and its incidence of comorbid with major depressive disorder (MDD) is significantly higher than the general population[2]. However, many patients lack proper recognition and necessary psychological health treatments. We aimed to identify potential biomarkers and mechanisms involved in the development of IBD comorbid with MDD (IBD-MDD). Methods We utilized IBD and MDD-related datasets from the GEO database for differential gene expression analysis, protein-protein interaction (PPI) and pathway enrichment analysis, random forest algorithm, LASSO regression analysis, and construction of a disease prediction model. We assessed the accuracy of the model using ROC curve, explored potential mechanisms through immune infiltration analysis, and validated candidate biomarkers using peripheral blood samples from patients in our center’s cohort. Results We identified 484 IBD-related secreted proteins and 142 key module genes associated with MDD. PPI analysis revealed two crucial modules primarily involved in inflammation and immune regulation. We identified four diagnostic genes (HGF, SPARC, ADAM12, and MMP8) from the 21 shared genes between IBD-related secreted proteins and MDD key module genes, constructed a nomogram model and confirmed its accuracy using ROC curve from an external independent dataset. Immune infiltration analysis revealed significant associations between the four diagnostic genes, and cellular immune dysregulation in MDD. Finally, we validated the expression patterns of the four diagnostic genes in our cohort.The results showed that the serum levels of HGF and MMP8 were significantly elevated in IBD patients with comorbid MDD, SPARC and ADAM12 showed an increasing trend (Figure 1A). Meanwhile, we developed a predictive model for IBD-related MDD based on our cohort (Figure 1B). The calibration curve suggests that the predictive probability of the nomogram model is nearly the same as that of the ideal model (Figure 1C). ROC curve analysis of the efficacy of the joint predictive model based on the 4 diagnostic markers showed that the AUC value was 0.87, indicating that the nomogram have strong diagnostic value for IBD-related MDD (Figure 1D). Conclusion Our study discovered four candidate biomarkers for IBD-MDD, providing new insights for the diagnosis and therapeutic intervention of serum-based IBD comorbid with MDD.

Genetic architecture and mechanisms shared between kidney and ureteral stones, cardiovascular diseases, and metabolic syndrome: A comprehensive GWAS analysis.

Genetic associations between asthma and type 2 inflammatory diseases: Insights from pleiotropic loci and genes: shared genetics of Type 2 Iinflammatory diseases: Shared Genetics of Type 2 Inflammatory Diseases.

Growing evidence suggests that epilepsy and psychiatric disorders may share common genetic underpinnings, yet the precise etiological relationship remains unclear. Psychiatric comorbidities affect approximately 30% of individuals with epilepsy, a rate markedly higher than in the general population, with depression (∼23%) and anxiety (∼20%) being the most prevalent. This high comorbidity burden not only worsens prognosis but also complicates management, underscoring the need for genetic insights into their relationship. To address this gap, we aimed to systematically evaluate the genetic correlation, pleiotropy, and potential causal associations between epilepsy and 14 major psychiatric disorders. We analyzed N million single-nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) summary statistics of epilepsy and 14 psychiatric disorders. These GWAS data were obtained from large international consortia, primarily comprising individuals of European ancestry. First, we assessed the genetic correlation between epilepsy and 14 psychiatric disorders using Linkage Disequilibrium Score Regression (LDSC). Second, we used Pleiotropic Analysis under the Composite Null Hypothesis (PLACO) to identify pleiotropic loci at the SNP level. Summary genotype-phenotype association statistics were used, excluding SNPs with extreme Z2 values (>80), and testing for pleiotropy with the Inverse-Variance Weighted (IVW) method. For gene-level pleiotropy, we conducted genome annotation multi-marker analysis (MAGMA v.1.07b). This analysis aggregated SNP-level associations into gene-level signals, focusing on 18,563 protein-coding genes on autosomes. Gene positions were obtained from the Ensembl build (GRCh37) and 1000G EUR data. Functional mapping and annotation of pleiotropic loci were performed using Functional Mapping and Annotation (FUMA). Finally, the bidirectional Mendelian randomization (MR) method was used to investigate causal correlations between epilepsy and 14 psychiatric disorders. We identified a significant genetic link between epilepsy and attention deficit and hyperactivity disorder (ADHD) (rg = 0.252, P < 0.001), between epilepsy and schizophrenia (SCZ) (rg = -0.060, p = 0.003), and between epilepsy and major depressive disorder (MDD) (rg = 0.167, p = 0.014). The genetic correlation between epilepsy and ADHD, epilepsy, and SCZ passed the Bonferroni correction (0.05/14 = 0.0035). Nine shared genetic loci and six pleiotropic genes, including SCN1A, PGBD1, ZKSCAN3, ZKSCAN4, VRK2, and ZSCAN23, have been identified between epilepsy and psychiatric disorders. Furthermore, these loci and genes mainly involve the MAPK signaling pathway. MR analysis showed ADHD (OR = 1.097, 95% CI: 1.019-1.180, p = 0.014) and MDD (OR = 1.277, 95% CI 1.114-1.463, p = 0.000) are the risk factors for epilepsy. BIP is the protecting factor against epilepsy (OR = 0.930, 95% CI: 0.878-0.986, p = 0.014). The causality between MDD and epilepsy passed the Bonferroni correction (0.05/14 = 0.0035). SCZ, ADHD, MDD and epilepsy may share a common etiology, respectively. These etiologies may be related to precise molecular mechanisms, leading to overlapping pathological physiology and clinical features. These findings may offer insights into treatment trials.

Major depressive disorder (MDD) is a common comorbidity in chronic obstructive pulmonary disease (COPD), affecting up to 57% of patients with COPD. Although the comorbidity of COPD and MDD is well established, the causal relationship between these two diseases is unclear. A large-scale electronic health record clinical biobank and genome-wide association study summary statistics for MDD and lung function traits were used to investigate potential shared underlying genetic susceptibility between COPD and MDD. Linkage disequilibrium score regression was used to estimate genetic correlation between phenotypes. Polygenic risk scores (PRS) for MDD and lung function traits were developed and used to perform a phenome-wide association study (PheWAS). Multi-trait-based conditional and joint analysis identified single-nucleotide polymorphisms (SNPs) influencing both lung function and MDD. We found genetic correlations between MDD and all lung function traits were small and not statistically significant. A PRS-MDD was significantly associated with an increased risk of COPD in a PheWAS [odds ratio (OR) = 1.12, 95% confidence interval (CI): 1.09-1.16] when adjusting for age, sex and genetic ancestry, but this relationship became attenuated when controlling for smoking history (OR = 1.08, 95% CI: 1.04-1.13). No significant associations were found between the lung function PRS and MDD. Multi-trait-based conditional and joint analysis identified three SNPs that may contribute to both traits, two of which were previously associated with mood disorders and COPD. Our findings suggest that the observed relationship between COPD and MDD may not be driven by a strong shared genetic architecture.

Characterizing the polygenic overlaps of bipolar disorder subtypes with schizophrenia and major depressive disorder

Major depressive disorder (MDD) is an emotional distinguished by core clinical symptoms such as low mood, diminished interest, lack of pleasure, reduced activity, and mental inhibition. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract with with an unknown etiology. Previous studies have indicated a positive association between MDD and IBD, although the specific underlying mechanism remains unclear. The objective of this research was to investigate shared differentially expressed genes (DEGs) common to MDD and IBD through bioinformatics analysis to elucidate the connection.The series matrix files of GSE3365 and GSE98793 were obtained from the NCBI GEO public database. The limma R package was utilized to identify DEGs common to MDD and IBD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation, protein–protein interaction analysis of the hub genes, weighted gene co-expression network analysis (WGCNA), correlation analysis of the hub genes with immune responses, and analysis of immune infiltrations were conducted. Gene set enrichment analysis was performed to elucidate the underlying pathogenesis. The intersection analysis identified 27 commonly upregulated genes and 13 downregulated genes. Subsequent GO and KEGG analyses revealed enrichment of infection-related signaling pathways among the DEGs. The integration of genes from the WGCNA module and differential genes resulted in the identification of eight commonly upregulated genes: PROS1, ORM2, SLP1, MMP9, CLEC5A, ARG1, OLR1, and EGF. Furthermore, immune infiltration analysis demonstrated an increase in neutrophil infiltration in both the MDD and IBD datasets. ORM2 and MMP9 were found to be correlated with neutrophil infiltration. These pivotal genes, associated with neutrophils and monocytes, play crucial roles in the pathophysiology of both conditions. Targeting ORM2 and MMP9 may hold promise as potential diagnostic and therapeutic strategies for managing the comorbidity of IBD and MDD.

Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer’s disease [AD], Parkinson’s disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.

Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, the degree to which the shared genetic determinants are involved in these associations underlying the GBA is unclear. To investigate the shared genetic etiology between gastrointestinal tract diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways. This genome-wide pleiotropic association study using genome-wide association summary statistics from publicly available data sources was performed with various statistical genetic approaches to sequentially investigate the pleiotropic associations from genome-wide single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]), and gene levels and biological pathways to disentangle the underlying shared genetic etiology between 4 gastrointestinal tract diseases (inflammatory bowel disease, irritable bowel syndrome, peptic ulcer disease, and gastroesophageal reflux disease) and 6 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, and anorexia nervosa). Data were collected from March 10, 2021, to August 25, 2021, and analysis was performed from January 8 through May 30, 2022. The primary outcomes consisted of a list of genetic loci, genes, and pathways shared between gastrointestinal tract diseases and psychiatric disorders. Extensive genetic correlations and genetic overlaps were found among 22 of 24 trait pairs. Pleiotropic analysis under a composite null hypothesis identified 2910 significant potential pleiotropic SNVs in 19 trait pairs, with 83 pleiotropic loci and 24 colocalized loci detected. Gene-based analysis found 158 unique candidate pleiotropic genes, which were highly enriched in certain GBA-related phenotypes and tissues, whereas pathway enrichment analysis further highlighted biological pathways primarily involving cell adhesion, synaptic structure and function, and immune cell differentiation. Several identified pleiotropic loci also shared causal variants with gut microbiomes. Mendelian randomization analysis further illustrated vertical pleiotropy across 8 pairwise traits. Notably, many pleiotropic loci were identified for multiple pairwise traits, such as 1q32.1 (INAVA), 19q13.33 (FUT2), 11q23.2 (NCAM1), and 1p32.3 (LRP8). These findings suggest that the pleiotropic genetic determinants between gastrointestinal tract diseases and psychiatric disorders are extensively distributed across the genome. These findings not only support the shared genetic basis underlying the GBA but also have important implications for intervention and treatment targets of these diseases simultaneously.