Mendelian Randomization Analyses Reveal the Causal Effect of Cathepsin Z on the Risk of Different Subtypes of Thyroid Cancer

Thyroid cancer (TC) remains a prevalent malignancy with a rising incidence worldwide, yet the causal relationship between the plasma lipidome and TC is still poorly understood. This study aims to explore this relationship using two-sample Mendelian randomization (MR) analysis. We analyzed genetic variants associated with 179 lipid species from a genome-wide association study (GWAS) of the plasma lipidome, as well as data on TC and its subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), from the FinnGen consortium. The primary analysis was conducted using the inverse variance weighted (IVW) method, with additional validation through other MR approaches. Sensitivity analyses were also performed to assess the robustness of the results. Our MR analysis revealed significant causal associations between the plasma lipidome and the risks of TC, PTC, and FTC. For TC, sphingomyelin (d36:1) was associated with a reduced risk (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.97, p = 0.0146), while triacylglycerol (56:8) (OR = 1.18, 95% CI = 1.02-1.37, p = 0.0233), triacylglycerol (50:1) (OR = 1.24, 95% CI = 1.03-1.49, p = 0.0244) and phosphatidylethanolamine (O-18:2_20:4) (OR = 1.31, 95% CI = 1.09-1.57, p = 0.0033) were associated with an increased risk. For PTC, sterol ester (27:1/20:3) was potentially protective (OR = 0.84, 95% CI = 0.73-0.97, p = 0.0137), while phosphatidylcholine (16:0_22:6) (OR = 1.29, 95% CI = 1.05-1.59, p = 0.0175) and phosphatidylethanolamine (O-18:2_20:4) (OR = 1.45, 95% CI = 1.17-1.78, p = 0.0005) were linked to a higher risk. For FTC, phosphatidylcholine (18:2_18:2) (OR = 1.67, 95% CI = 1.04-2.70, p = 0.0351), sterol ester (27:1/18:0) (OR = 1.69, 95% CI = 1.05-2.74, p = 0.0320), triacylglycerol (54:3) (OR = 1.71, 95% CI = 1.08-2.73, p = 0.0233), phosphatidylcholine (18:0_0:0) (OR = 1.80, 95% CI = 1.01-3.21, p = 0.0450), triacylglycerol (48:3) (OR = 1.96, 95% CI = 1.13-3.40, p = 0.0159), triacylglycerol (50:4) (OR = 2.12, 95% CI = 1.30-3.45, p = 0.0024), triacylglycerol (58:8) (OR = 2.17, 95% CI = 1.24-3.80, p = 0.0065), triacylglycerol (51:3) (OR = 2.19, 95% CI = 1.31-3.64, p = 0.0027), and triacylglycerol (49:1) (OR = 2.28, 95% CI = 1.16-4.49, p = 0.0167) were linked to an increased risk, with no protective lipid identified. This study underscores the distinct effects of lipid molecular structures on TC subtypes, offering insights into potential therapeutic strategies.

Systemic sclerosis(SSc) remains unclear, studies suggest that inflammation may be linked to its pathogenesis. Hence, we conducted a bidirectional Mendelian randomization (MR) analysis to evaluate the association between cytokine and growth factor cycling levels and the risk of SSc onset. In our study, the instrumental variables(IVs) for circulating cytokines were sourced from the genome-wide association study (GWAS) dataset of 8293 Finnish individuals. The SSc data comprised 302 cases and 213145 controls, and was included in the GWAS dataset. We employed four methods for the MR analysis: MR Egger, Inverse variance weighted (IVW), Weighted medium, and Weighted Mode, with IVW being the primary analytical method. Sensitivity analyses were performed using heterogeneity testing, horizontal pleiotropy testing, and the Leave One Out (LOO) method. We also conducted a reverse MR analysis to determine any reverse causal relationship between SSc and circulating cytokines. After Bonferroni correction, MR analysis revealed that the Interleukin-5 (IL-5) cycle level was associated with a reduced risk of SSc [odds ratio (OR)=0.48,95% confidence interval (CI): 0.27-0.84, P=0.01]. It also indicated that the Stem cell growth factor beta (SCGF-β) cycling level might elevate the risk of SSc (OR = 1.36, 95% CI: 1.01-1.83, P = 0.04). However, the reverse MR analysis did not establish a causal relationship between SSc and circulating cytokine levels. Additionally, sensitivity analysis outcomes affirm the reliability of our results. Our MR study suggests potential causal relationships between IL-5, SCGF-β, and the risk of SSc. Further research is essential to determine how IL-5 and SCGF-β influence the development of SSc.

Growing researches explore vitamin D's role in temporomandibular disorders (TMDs), but the link between vitamin D and TMDs remains debated. To clarify the causal relationship, we conducted a Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS). The GWAS dataset of vitamin D (GWAS ID: ukb-d-30890_irnt; sample size: 329247) was obtained from the IEU Open GWAS project. And that of TMDs (GWAS ID: finn-b-TEMPORO; sample size: 134280), initiated on August 25th, 2017 and publicly released on December 18th, 2023, was extracted from the FinnGen dataset, whose cases were diagnosed based on the revised International Classification of Diseases, 10th Edition (ICD-10) code K07.6. Both datasets were obtained from the European population. According to three assumptions of MR analysis, a bi-directional MR analysis was performed to measure the causal relationship, with Inverse variance weighted (IVW) as the primary method and MR Egger and Weighted median as supplement. Moreover, diverse sensitivity analyses, including Cochran's Q test, MR Egger intercept, Mendelian randomized polymorphism RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis, were used to verify the stability of the findings. The MR analysis supported causal effects of vitamin D levels on TMDs risks within the European population using IVW method [odds ratio = 1.316; 95% confidence interval = 1.086 to 1.595; P = 0.005], supported by MR Egger and Weighted median. While there was no indication that TMDs have a direct impact on vitamin D levels [β: -0.00738, standard error = 0.00665; P = 0.568]. The study revealed that within the European population higher levels of vitamin D led to higher risks of developing temporomandibular disorders, but found no obvious evidence that TMDs are causally associated with vitamin D. The conclusion should be cautiously interpreted, given the selection bias of TMDs patients sample.

Epidemiology of Thyroid Cancer.

Previous studies reported that many inflammatory factors have associations with osteoporosis. This study use Mendelian randomization (MR) analysis to explore the causal genetic relationship between 41 inflammatory factors and osteoporosis. A bidirectional two-sample MR analysis was performed by employing five Mendelian randomization analysis methods including MR Egger regression, weighted median, inverse-variance weighted and weight mode methods. Summary statistics from the genome-wide association study (GWAS) of 41 inflammatory cytokines and osteoporosis were included in this study. This study examined the MR analysis results for heterogeneity and horizontal pleiotropy. Using the inverse variance weighted (IVW) method, this analysis indicated that elevated monocyte chemotactic protein-1 (MCP-1) levels were potentially linked to a 22% increased likelihood of osteoporosis (Odds Ratio (OR) = 1.22, 95% CI: 1.04-1.43, p = 0.014). Additionally, through the IVW approach, we observed that higher tumor necrosis factor-related apoptosis inducing ligand (TRAIL) levels were possibly associated with a 15% greater risk of osteoporosis (OR = 1.12, 95% CI: 1.03-1.29, p = 0.012). Other 39 inflammatory cytokines don't have casual genetic association with osteoporosis. When this study use MR to estimate the influence of osteoporosis on inflammatory factors, none of the p-values with IVW method were lower than 0.05. This is the first bidirectional MR analysis to explore the causal genetic relationship between inflammatory cytokines and osteoporosis. This study found that MCP-1 and TRAIL are probably the upstream factors correlated with osteoporosis, and no inflammatory cytokine was involved in osteoporosis development downstream.

Hashimoto's thyroiditis (HT) is a prevalent autoimmune disorder and thyroid cancer (TC) is the most prevalent endocrine malignancy. Recent debates have focused on whether HT increases the risk of developing TC. This study combined Mendelian randomization (MR) and observational methods to investigate the potential causal relationship between HT and TC risk. First, we performed two-sample MR and multivariable MR (MVMR) analysis using the genome-wide association studies (GWAS) data from multiple databases, including European and East Asian populations, to estimate the effect of HT and thyroid-stimulating hormone (TSH) levels on TC risk. Second, we conducted an observational study using data from the National Health and Nutrition Examination Survey (NHANES) database and evaluated the association between HT, TSH, and TC prevalence through logistic regression model and restricted cubic spline model. Our MR findings revealed no significant association between HT and TC risk in both populations. However, elevated TSH levels significantly increased TC and papillary thyroid carcinoma (PTC) risk, while lower TSH levels were associated with reduced TC risk. Further MVMR analysis and an observational study confirmed this. Additionally, our observational study also indicated no significant relationship between HT and TC prevalence and abnormal TSH levels correlated with higher TC risk. HT was not a TC risk factor, but high TSH levels increased TC risk. Controlling TSH within normal ranges through thyroid hormone replacement was recommended to reduce TC risk in HT patients with elevated TSH levels, even those without symptoms.

Mendelian randomization analysis does not reveal a causal association between genetic liability to chronic pain and autism spectrum disorder.

The retina is a highly metabolically active tissue, and there is a lack of clarity about the relationship between metabolites and diabetic retinopathy (DR). This study used two-sample bidirectional Mendelian randomization (MR) analyses to identify causal relationships between metabolites and DR. Genetic variants were selected from the open-access Genome-Wide Association Studies (GWAS) summary database as proxies for the 1400 most recently published metabolites. MR analysis was performed to examine associations between these metabolite traits and DR. Single nucleotide polymorphism (SNP) data that were significantly associated with exposure were screened through association analysis. Validated instrumental variables (IVs) were obtained by removing SNPs with linkage disequilibrium (LD) and F-statistic values below 10. MR analyses were performed using the inverse variance weighted (IVW) method as the primary approach. The robustness of the results was verified by sensitivity analyses, including assessments of heterogeneity, horizontal pleiotropy, and the leave-one-out method. In the IVW approach and in the primary analysis of several sensitivity analyses, genetically determined glycolithocholate sulfate levels, androstenediol (3 beta, 17 beta) monosulfate (1) levels, 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4) levels, 1-oleoyl-2-arachidonoyl-GPE (18:1/20:4) levels, 1-oleoyl-2-linoleoyl-GPE (18:1/18:2) levels, X-26109 levels, N6-methyllysine levels, (N6,N6-dimethyllysine levels), and (N2-acetyl,N6,N6-dimethyllysine levels) were negatively associated with the risk of DR. 5-hydroxymethyl-2-furoylcarnitine levels and the glutamate-to-alanine ratio were positively associated with the risk of DR. No reverse causal association was found between DR and metabolites. This MR study suggests that nine metabolites may have a protective effect in DR, while two metabolites may be associated with an increased risk of DR. However, further research is needed to confirm these findings. Supplementation with beneficial metabolites may reduce DR risk and could potentially be a novel therapeutic approach to DR treatment.

In order to address the ongoing debate surrounding the potential link between COVID-19 and thyroid cancer, our study was specifically designed to investigate the association between these two factors. We acquired summary data from a genome-wide association study (GWAS) concerning COVID-19 susceptibility and severity of COVID-19 in the European population, with a focus on their relationship with thyroid cancer. We applied three distinct methodologies to evaluate the causality between COVID-19 and thyroid cancer, employing Mendelian randomization (MR)-Egger, weighted median (WM), and inverse variance-weighted (IVW) approaches. Furthermore, we utilized a variety of techniques to assess pleiotropy and heterogeneity, including the MR-Egger intercept, MR-pleiotropy residual sum and outlier method (PRESSO), and Cochran's Q test. The MR analysis revealed associations between the susceptibility of COVID-19 and thyroid cancer (IVW odds ratio [OR]: 2.826, 95% confidence interval [CI]: [0.842, 9.483], P = 0.093) as well as between the risk of COVID-19 hospitalization and thyroid cancer (IVW OR: 1.630, 95% CI: [1.050, 2.529], P = 0.029). However, the relationship between COVID-19 and the occurrence of severe thyroid cancer cases was less evident (IVW OR: 1.061, 95% CI: [0.575, 1.956], P = 0.850). Our sensitivity analyses did not reveal any signs of horizontal pleiotropy or heterogeneity. Our MR study provided compelling evidence supporting a causal connection between the risk of COVID-19 hospitalization and thyroid cancer. Nevertheless, the MR results derived from genetic data do not support a causal link between susceptibility to COVID-19 and the risk of thyroid cancer or between very severe cases of COVID-19 and the risk of thyroid cancer. These findings have significant implications for further investigations into the impact of COVID-19 on health and the etiology of thyroid cancer.

Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. Utilizing summary-level data from large-scale genome-wide association studies in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighted was used as the primary method for MR analysis. In addition, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction.

Previous observational researchers have found an inverse bidirectional link between Alzheimer's disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted. This study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran's Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results. The causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables. The results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.

Previous investigations have demonstrated a correlation between the composition of gut microbiota and the development of thyroid cancer (TC). Nonetheless, there was no consensus on the causal effect of gut microbiota composition on TC risk. Therefore, the present study aimed to perform a bidirectional two-sample Mendelian randomization (MR) analysis to explore potential causal associations between gut microbiota and TC risk. Utilizing data from the MiBioGen consortium's genome-wide association studies (GWAS) meta-analysis involving a sample size of 18,340, we identified instrumental variables for 211 gut microbiota taxa. The summary statistics for TC was from relevant large-scale GWAS conducted by the FinnGen consortium. In the first stage, the Inverse-variance weighted (IVW) method was used as the primary estimate method, and the stability of estimations was tested by a battery of sensitivity analyses. In the second stage, a reverse MR analysis was applied to determine whether reverse causality existed. According to the IVW method, we identified 9 genetically predicted gut microbiota that were causally correlated with TC risk. Among them, we observed a positive causal effect of Family Christensenellaceae (OR = 1.664, 95% CI: 1.103-2.511, P = 0.015), Family Victivallaceae (OR = 1.268, 95% CI: 1.009-1.594, P = 0.042), Genus Methanobrevibacter (OR = 1.505, 95% CI: 1.049-2.159, P = 0.027), Genus Ruminococcus2 (OR = 1.846, 95% CI: 1.261-2.704, P = 0.002), Genus Subdoligranulum (OR = 1.907, 95% CI: 1.165-3.121, P = 0.010), Phylum Verrucomicrobia (OR = 1.309, 95% CI: 1.027-1.668, P = 0.029) on TC risk, while Class Betaproteobacteria (OR = 0.522, 95% CI: 0.310-0.879, P = 0.015), Family Family XI (OR = 0.753, 95% CI: 0.577-0.983, P = 0.037), Genus Sutterella (OR = 0.596, 95% CI: 0.381-0.933, P = 0.024) might be correlated with a decreased risk of TC. Subsequently, various sensitivity analyses indicated no heterogeneity, directional pleiotropy or outliers. In addition, reverse analysis demonstrated a negative causal effect of TC risk on the abundance of the gut microbiota (Genus Ruminococcus2, OR = 0.947, 95% CI: 0.907-0.989, P = 0.014). Genetic evidence suggested that bidirectional causal associations of specific bacteria taxa and the risk of TC, highlighting the association of the "gut-thyroid" axis. Further exploration of the potential microbiota-related mechanisms might have profound implications for public health in terms of the early prevention and treatment of TC.

Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis. Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations. In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family Lachnospiraceae (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus Erysipelatoclostridium might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the Genus Butyricicoccus had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05). We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.

IntroductionRecent observational studies have reported the association between ischemic stroke (IS) and cerebral microbleeds (CMBs). Whether this reflects a causal association remains to be established. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) analysis to comprehensively evaluate the causal association of IS and CMBs.MethodsThe summary-level genome-wide association studies (GWASs) data of IS were obtained from the GIGASTROKE consortium (62,100 European ancestry cases and 1,234,808 European ancestry controls). All IS cases could be further divided into large-vessel atherosclerosis stroke (LVS, n = 6399), cardio-embolic stroke (CES, n = 10,804) and small-vessel occlusion stroke (SVS, n = 6811). Meanwhile, we used publicly available summary statistics from published GWASs of CMBs (3556 of the 25,862 European participants across 2 large initiatives). A bidirectional MR analysis was conducted using inverse-variance weighting (IVW) as the major outcome, whereas MR-Egger and weighted median (WM) were used to complement the IVW estimates as they can provide more robust estimates in a broader set of scenarios but are less efficient (wider CIs). A Bonferroni-corrected threshold of p < 0.0125 was considered significant, and p values between 0.0125 and 0.05 were considered suggestive of evidence for a potential association.ResultsWe detected that higher risk of IS [IVW odds ratio (OR) 1.47, 95% confidence interval (CI) 1.04–2.07, p = 0.03] and SVS (IVW OR 1.62, 95% CI 1.07–2.47, p = 0.02) were significantly associated with CMBs. Reverse MR analyses found no significant evidence for a causal effect of CMBs on IS and its subtypes.ConclusionsOur study provides potential evidence that IS and SVS are causally linked to increased risk of CMBs. Further research is needed to determine the mechanisms of association between IS and CMBs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-023-00500-w.

Observational studies have shown a link between constipation (CN) and psychiatric disorders, including Schizophrenia (SP), Bipolar disorder (BD), Schizoaffective disorder (SD), and Parkinson's disease (PD). However, it is still unknown whether CN affects the occurrence and development of psychiatric disorders or whether psychiatric disorders cause the occurrence and development of CN. Therefore, this study used Mendelian randomization (MR) analysis to evaluate the relationship between CN and psychiatric disorders. We used genome-wide association studies (GWAS) to assess the relationship between constipation (N = 411, 623) and four psychiatric disorders, including SP ( N = 77, 096), BD (N = 51, 710), SD ( N = 210, 962), PD (N = 482, 730 ), using bidirectional MR analysis. Inverse variance weighting (IVW), MR Egger (ME) and Weighted median (WM) were used as causal analysis methods. Cochran's Q test, funnel plot, MR Egger intercept test and Leave-one-out analysis were used to detect sensitivity. Confounding factors were analyzed and eliminated by LDtrait to avoid influencing the final MR Analysis result. The results of positive MR analysis indicated that there was no evidence of influence of constipation on SP ( OR 1.043, 95%CI 0.946 - 1.149, P value = 0.398), BD (OR 1.114, 95%CI 0.995 - 1.248, P value = 0.062), SD (OR 0.934, 95%CI 0.674 - 1.294, P value = 0.682) and PD (OR 1.118, 95%CI 0.918 - 1.361, P value = 0.269) under gene prediction. Reverse MR analysis suggested that SP (OR 1.030, 95% CI 1.001-1.060, P value = 0.042) had a causal relationship with constipation. BD (OR 0.993, 95% CI 0.962-1.025, P value = 0.664), SD (OR 1.021, 95% CI 0.984-1.059, P value = 0.265) and PD (OR 1.004, 95% CI 0.974-1.035, P value = 0.790) were not associated with CN. There was a positive association between SP and CN. CN may have no exact causal relationship with BD, SD and PD, and the interaction mechanism between these diseases needs to be further explored.