Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

Li W ，He X ，Tan C ，Zhang T ... -  《-》

Exploring the causal relationship between Takayasu arteritis and inflammatory bowel disease using Mendelian randomization.

Takayasu arteritis (TA) and inflammatory bowel disease (IBD) are two distinct diseases; however, previous studies have reported many cases of IBD-TA coexistence. Additionally, the incidence of IBD in patients with TA is estimated to be significantly higher than the incidence in the general population. Therefore, the two diseases are anticipated to be linked. Mendelian randomization (MR) analysis assesses whether an exposure might causally affect an outcome by using genetic variants inherited randomly at conception, thereby reducing the impact of confounding and reverse causality. The present study aimed to investigate the potential causal relationship between TA and IBD using MR analysis. Two-sample MR analysis, in which TA and IBD were regarded as the exposure and outcome, respectively, was conducted to investigate whether the two diseases are causally related using the R TwoSampleMR package. Summary GWAS data of TA consisted of 516 Turkish cohorts and 462 controls, and 119 patients and 993 controls of European ancestry. Summary data of IBD was from a sub-study of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) that comprised 31,665 cases and 33,977 controls of European ancestry. Additionally, separate MR analyses stratified by the two major subtypes of IBD, Crohn's disease (CD) and ulcerative colitis (UC), were performed. Various statistical tests, including the intercept of MR-Egger regression, funnel plots, Cochran's Q tests, and leave-one-out sensitivity analyses, were employed to assess the presence of heterogeneity and horizontal pleiotropy among single nucleotide polymorphisms (SNPs). In the primary analysis using the inverse-variance weighted (IVW) method, the risk of developing IBD for a patient with TA compared to a non-TA control increased 1.053 times (Odds Ratio (OR) = 1.053, P = 0.065). The MR-Egger method (OR = 1.025, P = 0.470) yielded results consistent with this null finding. However, both the weighted median method (OR = 1.038, P = 0.002) and the weighted mode method (OR = 1.051, P = 0.009) identified a significant harmful causal effect. The MR outcomes from separate subgroup analyses slightly diverged from those of IBD and TA. Specifically, for CD, three methods indicated that TA is a risk factor: IVW estimated the OR as 1.045 (P = 0.032), MR-Egger as 0.997 (P = 0.957), weighed median as 1.028 (P = 0.021), and weighted mode as 1.031 (P = 0.022), respectively. This study represents one of the initial investigations into the potential causal association between TA and IBD. With three MR methods, including the primary IVW approach, indicating a notable effect on TA on CD, our analysis findings offer some indication that TA could be a contributing risk factor for CD.

Pang X ，Yang H ，Wang C ，Tian S ... -  《-》

Inflammatory bowel disease increases the risk of pancreatitis: a two-sample bidirectional Mendelian randomization analysis.

Previous studies have suggested an association between inflammatory bowel disease (IBD), and pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). We aimed to examine the potential causal relationship between IBD and pancreatitis using the Mendelian randomization (MR) method. We obtained data from genome-wide association studies (GWASs) in European individuals for IBD and its main subtypes, Crohn's disease (CD) and ulcerative colitis (UC) (31,665 IBD cases, 13,768 UC cases, 17,897 CD cases and 33,977 controls). Four independent summary statistics of pancreatitis from the the European Bioinformatics Institute (EMBL-EBI, 10,630 AP cases and 844,679 controls, 1,424 CP cases and 476,104 controls) and FinnGen Consortium (8,446 AP cases, 4,820 CP cases and 437,418 controls) were used for bidirectional MR analyses and sensitivity analysis. Finally, further meta-analysis was conducted on the MR results. Generally, IBD is associated with an increased risk of pancreatitis (IBD-AP, OR = 1.050, 95% CI 1.020-1.080, P = 7.20 × 10-5; IBD-CP, OR = 1.050, 95% CI 1.010-1.090, P = 0.019). In addition, UC increased the risk of pancreatitis (UC-AP, OR = 1.050, 95% CI 1.020-1.070, P = 9.10 × 10-5; UC-CP, OR = 1.090, 95% CI 1.040-1.140, P = 1.44 × 10-4) and CD increased the risk of acute pancreatitis (OR = 1.040, 95% CI 1.020-1.060, P = 9.61 × 10-5). However, no causal association was found between CD and the risk of chronic pancreatitis (P > 0.05). The reverse MR results showed that AP may be associated with a reduced risk of IBD and CD (AP-IBD, OR = 0.880, 95% CI 0.810-0.960, P = 0.003; AP-CD, OR = 0.830, 95% CI 0.730-0.940, P = 0.003). However, there is no causal relationship between AP and the risk of UC, and there is no causal relationship between CP and the risk of IBD and its subtypes(P > 0.05). In conclusion, based on MR analysis and meta-analysis, our results showed a positive causal effect of IBD on pancreatitis, and subgroup analyses showed that UC and CD may promote the development of acute pancreatitis, whereas UC may promote the development of chronic pancreatitis. Reverse MR analysis suggests that AP may have a potential protective effect on IBD and CD.

Fang LH ，Zhang JQ ，Huang JK ，Tang XD ... -  《BMC GASTROENTEROLOGY》

Effects of immune cells in mediating the relationship between inflammatory bowel disease and pyoderma gangrenosum: a two-sample, two-step mendelian randomization study.

Although the precise cause of the co-occurrence of pyoderma gangrenosum (PG) and inflammatory bowel disease (IBD) is still unknown, prior research has shown that the two conditions coexist. Moreover, it is currently unknown how immune cells function in influencing the relationship between IBD and PG. In order to choose independent single nucleotide polymorphism (SNP) as instrumental variables, we were provided with genome-wide association study (GWAS) summary data of European populations from the IEU OpenGWAS project (for IBD) and a the FinnGen database (for PG) publically available. For the MR analysis, a range of analytical techniques were employed to peer into the possible causative relationship between PG and IBD. The two-step MR analysis was used to investigate the mediating role of immune cells between IBD and PG. The chief method utilized was the inverse variance weighted (IVW) approach. Using the Cochran's Q test and the MR-Egger intercept, respectively, heterogeneity or pleiotropy was evaluated to support the findings. MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) were used to identify the outlier SNP. IBD was found to raise the incidence of PG (IVW-FE: OR = 1.604, 95%CI = 1.308-1.966, p = 5.58 × 10- 6), according to MR findings. Moreover, UC or CD were strongly correlated with a greater risk of PG (OR = 1.339, 95%CI = 1.041-1.723, p = 0.023 for UC; OR = 1.339, 95%CI = 1.107-1.621, p = 0.003 for CD). The results of the reverse MR study did not suggest a connection between PG and IBD. CD4+ regulatory T cell is the mediator that particularly stood out in the interaction between UC and PG. There was evidence of neither heterogeneity nor horizontal pleiotropy. And the validity of these conclusions was verified. In the European population, PG risk may be genetically elevated by IBD, including CD and UC, according to the current study. The effect of UC on PG may have been causally mediated by CD4+ regulatory T cells.

Zhu H ，Pan J 《-》

Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study.

Eosinophilic esophagitis (EoE) and inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are immune-mediated gastrointestinal diseases with overlapped pathogenesis and are sometimes concurrently diagnosed, but their causal relationship remains unclear. We investigated the causal relationship between EoE and IBD and its subtypes via a two-sample bidirectional Mendelian randomization (MR) approach. MR analyses were performed using summary data of a genome-wide association study (GWAS) on individuals of European ancestry. Independent single-nucleotide polymorphisms correlated with EoE (from a GWAS meta-analysis containing 1,930 cases and 13,634 controls) and IBD (from FinnGen GWASs containing 9,083 IBD, 2,033 CD, and 5,931 UC cases, and GWASs of IBD genetic consortium containing 12,882 IBD, 6,968 UC, and 5,956 CD cases) were selected as instruments. We applied the inverse variance weighted (IVW) method as the primary analysis followed by several sensitivity analyses. For the forward MR study, estimates from IVW methods were subsequently meta-analyzed using a random-effect model. Our results suggested a causal effect of EoE on IBD [pooled odds ratio (OR), 1.07; 95% confidence interval (CI), 1.02-1.13] and EoE on UC (pooled OR, 1.09, 95% CI, 1.04-1.14). No causal link between EoE and CD was observed (pooled OR, 1.05; 95% CI, 0.96-1.16). The reverse MR analyses revealed no causal effect of IBD (and its subtypes) on EoE. Sensitivity analyses confirmed the robustness of primary results. Our findings provided evidence of a suggestive causal effect of EoE on IBD (specifically on UC) in the European population. Increased awareness of concurrent or subsequent IBD in patients with EoE is called for. Still, the present evidence is not adequate enough and ought to be validated by further investigations.

Ji R ，Zhi Y 《Frontiers in Immunology》