Investigation of the causal association between Parkinson's disease and autoimmune disorders: a bidirectional Mendelian randomization study.

To date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson's disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk. By employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results. Our MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility. In general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.

Yang J ，Lin W ，Ma Y ，Song H ，Mu C ，Wu Q ，Han C ，Zhang J ，Liu X ... -  《Frontiers in Immunology》

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》

Causal associations between both psoriasis and psoriatic arthritis and multiple autoimmune diseases: a bidirectional two-sample Mendelian randomization study.

Numerous observational studies have identified associations between both psoriasis (PsO) and psoriatic arthritis (PsA), and autoimmune diseases (AIDs); however, the causality of these associations remains undetermined. We conducted a bidirectional two-sample Mendelian Randomization study to identify causal associations and directions between both PsO and PsA and AIDs, such as systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), uveitis, bullous pemphigoid (BP), Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA), vitiligo, and ankylosing spondylitis (AS). The causal inferences were drawn by integrating results from four regression models: Inverse Variance Weighting (IVW), MR-Egger, Weighted Median, and Maximum Likelihood. Furthermore, we performed sensitivity analyses to confirm the reliability of our findings. The results showed that CD [IVW odds ratio (ORIVW), 1.11; 95% confidence interval (CI), 1.06-1.17; P = 8.40E-06], vitiligo (ORIVW, 1.16; 95% CI, 1.05-1.28; P = 2.45E-03) were risk factors for PsO, while BP may reduce the incidence of PsO (ORIVW, 0.91; 95% CI, 0.87-0.96; P = 1.26E-04). CD (ORIVW, 1.07; 95% CI, 1.02-1.12; P = 0.01), HT (ORIVW, 1.23; 95% CI, 1.08-1.40; P = 1.43E-03), RA (ORIVW, 1.11; 95% CI, 1.02-1.21, P = 2.05E-02), AS (ORIVW, 2.18; 95% CI, 1.46-3.27; P = 1.55E-04), SLE (ORIVW, 1.04; 95% CI, 1.01-1.08; P = 1.07E-02) and vitiligo (ORIVW, 1.27; 95% CI, 1.14-1.42; P = 2.67E-05) were risk factors for PsA. Sensitivity analyses had validated the reliability of the results. Our study provides evidence for potential causal relationships between certain AIDs and both PsO and PsA. Specifically, CD and vitiligo may increase the risk of developing PsO, while CD, HT, SLE, RA, AS, and vitiligo may elevate the risk for PsA. Additionally, it is crucial to closely monitor the condition of PsO patients with specific AIDs, as they have a higher likelihood of developing PsA than those without AIDs. Moving forward, greater attention should be paid to PsA and further exploration of other PsO subtypes is warranted.

Duan K ，Wang J ，Chen S ，Chen T ，Wang J ，Wang S ，Chen X ... -  《Frontiers in Immunology》

Causal effects of autoimmune diseases on temporomandibular disorders and the mediating pathways: a Mendelian randomization study.

The role of autoimmune diseases (ADs) in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder is destructive in TMDs. This Mendelian randomization (MR) study aims to estimate the causal effect of common ADs on TMDs. Genetic data from published genome-wide association studies for fourteen common ADs, specifically multiple sclerosis (MS, N = 15,283), ankylosing spondylitis (AS, N = 22,647), asthma (N = 408,422), celiac disease (N = 15,283), Graves' disease (N = 458,620), Hashimoto thyroiditis (N = 395,640), primary biliary cirrhosis (PBC, N = 11,375), primary sclerosing cholangitis (PSC, N = 14,890), psoriasis vulgaris (N = 483,174), rheumatoid arthritis (RA, N = 417,256), systemic lupus erythematosus (SLE, N = 23,210), Type 1 diabetes (T1D, N = 520,580), inflammatory bowel disease (IBD, N = 34,652), and Sjogren's syndrome (SS, N = 407,746) were collected. Additionally, the latest summary-level data for TMDs (N = 228,812) were extracted from the FinnGen database. The overall effects of each immune traits were assessed via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Finally, 731 immune cell phenotypes (N = 3,757) were analyzed for their mediating role in the significant causality. Univariable MR analyses revealed that genetically predicted RA (IVW OR: 1.12, 95% CI: 1.05-1.19, p < 0.001) and MS (IVW OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were associated with increased risk of TMDs. Two out of 731 immune cell phenotypes were identified as causal mediators in the associations of RA with TMDs, including "CD25++ CD8+ T cell % CD8+ T cell" (mediation proportion: 6.2%) and "CD3 on activated CD4 regulatory T cell" (5.4%). Additionally, "CD127 on granulocyte" mediated 10.6% of the total effect of MS on TMDs. No reverse directions, heterogeneity, and pleiotropy were detected in the analyses (p > 0.05). This MR study provides new evidence regarding the causal impact of genetic predisposition to RA or MS on the increased risk of TMDs, potentially mediated by the modulation of immune cells. These findings highlight the importance for clinicians to pay more attention to patients with RA or MS when consulting for temporomandibular discomfort. The mediating role of specific immune cells is proposed but needs further investigation.

Chen X ，Cheng Z ，Xu J ，Wang Q ，Zhao Z ，Jiang Q ... -  《Frontiers in Immunology》

Association between Gastric Cancer and 12 Autoimmune Diseases: A Mendelian Randomization Study.

Wei Q ，Wang Z ，Liu X ，Liang H ，Chen L ... -  《Genes》