Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study.

Several studies have shown that neurodegenerative diseases (e.g., Parkinson's disease [PD] and Alzheimer's disease [AD]) are associated with inflammatory bowel disease (IBD), but the causality and direction of their associations remain unclear. Mendelian randomization (MR) studies have explored the causal effects of IBD on PD and AD. However, only a few studies examined this reverse association. Thus, this study aimed to explore whether there are causal associations of genetically predicted PD and AD with IBD, using a two-sample MR study. Summary statistics for IBD, ulcerative colitis (UC), and Crohn's disease (CD) were derived from a genome-wide association study (GWAS) meta-analysis, which included the International IBD Genetics Consortium and the UK IBD Genetics Consortium (n=59,957). Genetic variants associated with the largest meta-analysis of GWAS of PD (n=1,474,097) and AD (n=455,258) were used as instrumental variables. We used multiple methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and Robust Adjusted Profile Score (RAPS) methods, to estimate the effects of genetically predicted PD and AD on IBD. To confirm the validity of the analysis, we also evaluated the pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis that drive causal associations. The results of the IVW method, WM, and RAPS showed that genetically predicted PD was significantly associated with an increased risk of UC (odds ratio [OR]IVW=1.068, OR WM=1.107, OR RAPS=1.069, all P<0.05). Additionally, we found that there were significant associations of genetically predicted PD with CD (OR IVW=1.064, OR RAPS=1.065, all P<0.05) and IBD (OR IVW=1.062, OR RAPS=1.063, all P<0.05) using the IVW method and RAPS. However, there was no significant causal evidence of genetically predicted AD in IBD, UC, or CD among all MR methods. In all MR analyses, there were no horizontal pleiotropy (all P>0.05), or statistical heterogeneity. The sensitivity analysis results of the leave-one-out sensitivity analysis showed that the causal effect estimations of genetically predicted PD and AD on IBD were robust. Our MR study corroborated a causal association between genetically predicted PD and IBD but did not support a causal effect of genetically predicted AD on IBD. More animal experiments or population-based observational studies are required to clarify the underlying mechanisms of PD and IBD.

Cui G ，Li S ，Ye H ，Yang Y ，Huang Q ，Chu Y ，Shi Z ，Zhang X ... -  《Frontiers in Immunology》

Investigating the shared genetic architecture between primary sclerosing cholangitis and inflammatory bowel diseases: a Mendelian randomization study.

Several studies have found that primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are closely associated. However, the direction and causality of their interactions remain unclear. Thus, this study employs Mendelian Randomization to explore whether there are causal associations of genetically predicted PSC with IBD. Genetic variants associated with the genome-wide association study (GWAS) of PSC were used as instrumental variables. The statistics for IBD, including ulcerative colitis (UC), and Crohn's disease (CD) were derived from GWAS. Then, five methods were used to estimate the effects of genetically predicted PSC on IBD, including MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and Weighted mode. Last, we also evaluated the pleiotropic effects, heterogeneity, and a leave-one-out sensitivity analysis that drives causal associations to confirm the validity of the analysis. Genetically predicted PSC was significantly associated with an increased risk of UC, according to the study (odds ratio [OR] IVW= 1.0014, P<0.05). However, none of the MR methods found significant causal evidence of genetically predicted PSC in CD (All P>0.05). The sensitivity analysis results showed that the causal effect estimations of genetically predicted PSC on IBD were robust, and there was no horizontal pleiotropy or statistical heterogeneity. Our study corroborated a causal association between genetically predicted PSC and UC but did not between genetically predicted PSC and CD. Then, we identification of shared SNPs for PSC and UC, including rs3184504, rs9858213, rs725613, rs10909839, and rs4147359. More animal experiments and clinical observational studies are required to further clarify the underlying mechanisms of PSC and IBD.

Dong X ，Gong LL ，Hong MZ ，Pan JS ... -  《BMC GASTROENTEROLOGY》

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 ... -  《-》

Causal effects for neurodegenerative diseases on the risk of myocardial infarction: a two-sample Mendelian randomization study.

Chi J ，Hu J ，Wu N ，Cai H ，Lin C ，Lai Y ，Huang J ，Li W ，Su P ，Li M ，Xu L ... -  《Aging-US》

Causal association between inflammatory bowel disease and herpes virus infections: a two-sample bidirectional Mendelian randomization study.

Previous observational or retrospective studies have suggested an association between inflammatory bowel disease (IBD) and herpes virus infections. Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between IBD and herpes virus infections. In genome-wide association study (GWAS) datasets of the International Inflammatory Bowel Disease Genetics Consortium, we obtained genetic instrumental variables for three phenotypes from 34,652 participants (12,882 IBD cases and 21,770 controls), 27,432 participants [6,968 ulcerative colitis (UC) cases and 20,464 controls], and 20,883 participants [5,956 Crohn's disease (CD) cases and 14,927 controls], respectively. Summary statistics for herpes virus infections (chickenpox, herpes zoster, and mononucleosis) were obtained from the FinnGen database. MR results were expressed as odds ratio (OR) with 95% confidence interval (CI). Our study found no evidence of a causal effect of genetically predicted IBD on herpes virus infections [P value for inverse variance weighting (IVW): 0.063 to 0.652]. For the subtypes of IBD, UC had a suggestive association with mononucleosis (P value for IVW: 0.023). It appeared that CD was also weakly associated with mononucleosis (P value for IVW: 0.058; P value for Weighted median: 0.036). In addition, we found a suggestive causality for CD on chickenpox (P value for IVW: 0.038). Neither UC (P value for IVW: 0.574) nor CD (P value for IVW: 0.168) has a causal effect on herpes zoster. The results of the bidirectional MR analysis did not indicate that herpes virus infections were associated with IBD, UC or CD (P value for IVW: 0.239 to 0.888). This study showed a suggestive causality for both CD-chickenpox and UC-mononucleosis, despite no associations reaching a statistical significance value after corrections for multiple testing. There was no evidence of a causal association between IBD and its two subtypes on herpes zoster.

Zou M ，Zhang W ，Shen L ，Xu Y ，Zhu Y ... -  《Frontiers in Immunology》