Bidirectional Mendelian Randomization Research Articles

Assessing the Genetic Causal Effects Between Blood Metabolites and Spinal Pain: A Bidirectional Two-Sample Mendelian Randomization Study.

Previous metabolomics studies have indicated a close association between blood metabolites and pain. However, the causal relationship between blood metabolites and spinal pain (SP) remains unclear. This study employs a bidirectional two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between 452 blood metabolites and SP. We used bidirectional two-sample MR analysis to assess the causal relationship between blood metabolites and SP, including neck pain (NP), thoracic spine pain (TSP), low back pain (LBP), and back pain (BP). Genome-wide association studies (GWAS) data for 452 metabolites (7,824 participants) were used as exposure variables. Summary data for NP were obtained from the UK Biobank, for TSP from the FinnGen Biobank, and for LBP from both the UK Biobank and the FinnGen Biobank. Summary data for BP were obtained from the UK Biobank. Inverse-variance weighting (IVW) was used to estimate the causal relationships between metabolites and SP, complemented by various sensitivity analyses to account for pleiotropy and heterogeneity, ensuring robust results. The IVW analysis identified 155 metabolites associated with SP risk and 142 metabolites influenced by SP. No significant heterogeneity or horizontal pleiotropy was observed through other analytical methods. This study demonstrates potential causal effects between blood metabolites and SP, providing new insights into the pathogenesis of SP. These findings lay a theoretical foundation for preventing and treating SP through targeted interventions on specific blood metabolites, potentially elucidating underlying biological mechanisms.

Investigating the causal association between heme oxygenase-1 and asthma: A bidirectional two-sample Mendelian randomization analysis in a European population

BackgroundThe association between heme oxygenase-1 (HO-1) and asthma has been a subject of debate in both observational and experimental studies. We aimed to evaluate the potential causal relationship between HO-1 and asthma. Materials and methodsA bidirectional two-sample Mendelian randomization (TSMR) study was conducted to examine the causal relationship between HO-1 and asthma. In the forward Mendelian randomization (MR) analyses, HO-1 was considered as the exposure, while asthma as the outcome. Conversely, in the reverse MR analyses, asthma was regarded as the exposure, and HO-1 as the outcome. Data for HO-1 and asthma were obtained from publicly accessible genome-wide association studies (GWAS). These causal relationships were identified through 5 MR methods, namely MR-Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode. Additionally, sensitivity tests were conducted to assess the robustness of MR study. Finally, additional asthma datasets and childhood asthma were selected to validate the findings. ResultsIn the forward MR analyses, according to the IVW method, genetically predicted HO-1 displays a negative correlation with the risk of asthma (OR 0.947, 95% CI 0.905–0.990). It was not found any SNP overly sensitive or disproportionately responsible for the outcome. No evidence of heterogeneity and pleiotropy between SNPs was observed. Genetically predicted asthma was not associated with HO-1 in reverse MR analyses using the IVW method. The same results were validated in additional asthma datasets and in childhood asthma. ConclusionThe results of MR analysis revealed heme oxygenase-1 as a protective factor for asthma.

Autoimmune diseases and cardiovascular risk: Mendelian randomization analysis for the impact of 19 autoimmune diseases on 14 cardiovascular conditions

BackgroudAutoimmune diseases (AIDs) have been associated with various cardiovascular diseases (CVDs) in observational data. However, the causality of these associations remains uncertain. Therefore, a systematic assessment of the impact of AIDS on cardiovascular risk is required. ResultsWe assessed the impact of 19 common AIDs on 14 CVDs using bidirectional Mendelian randomization (MR). Celiac disease (odds ratio [OR] = 2.949, 95 % confidence interval [CI]: 1.111–7.827, P = 0.030) and type 1 diabetes mellitus (T1DM) (OR = 1.044, 95 % CI: 1.021–1.068, P = 1.82e-4) were associated with an increased risk of peripheral arterial disease (PAD). Additionally, celiac disease was linked to an increased risk of arrhythmia (OR = 1.008, 95 % CI: 1.002–1.013, P = 0.004), multiple sclerosis to venous thromboembolism (OR = 1.001, 95 % CI: 1.000–1.001, P = 0.010), and psoriasis to heart failure (OR = 1.048, 95 % CI: 1.021–1.077, P = 0.001). Sensitivity analyses were conducted to enhance the robustness of these findings. Predominantly, immune response and inflammation-related pathways were enriched in the aforementioned associations. Mediation analysis identified human leukocyte antigen-DR positive myeloid dendritic cells as partially mediating the effect of T1DM on PAD, with a mediated proportion of 16.61 % (P = 0.028). Potential therapeutic agents, such as tumor necrosis factor-alpha inhibitors and interferon, may have efficacy in treating AID-related CVDs. ConclusionsThis study presents genetic evidence of certain AIDs impacting specific CVDs and identifies potential mediators and drugs.

Can early gut microbiota screening reduce the incidence of cognitive impairment? A Mendelian randomization study.

Background: Gastrointestinal symptoms are now detected early in the clinical course of many dementia patients, and studies of the microbiome-gut-brain axis have confirmed bidirectional interactions between the gut and the brain. However, the causal relationship between gut microbiota and cognitive impairment has not been fully established. Therefore, this study conducted a bidirectional Mendelian randomization study to elucidate the potential causal relationship of gut microbiota to cognitive impairment. Objective: Using Mendelian randomization to identify gut flora with a genetic causal effect on the development of cognitive impairment. Methods: This study utilized publicly available genome-wide association study summary data to perform MR analysis, with gut microbiota as the exposure and various cognitive function indicators as well as scores for Alzheimer's disease as outcomes. This study selected single nucleotide polymorphisms as instrumental variables based on p-values, F-statistics, and r2. Bidirectional Mendelian randomization was conducted using methods such as inverse variance weighted, MR-Egger, simple mode, and weighted mode to assess the causal relationship. Concurrently, this study carried out Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to identify potential heterogeneity and horizontal pleiotropy. Results: This study identified a total of 31 gut microbes that have a causal relationship with cognitive impairment, which include 1 phylum, 4 classes, 3 orders, 2 families, and 21 genera. Conclusions: This study unveiled specific gut microbiota associated with cognitive impairment, offering new insights and approaches for the prevention and treatment of cognitive impairment through gut microbiota such as Bifidobacterium and Ruminococcus gnavus group.

Genetic associations of metabolic factors and therapeutic drug targets with polycystic ovary syndrome

IntroductionPolycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. ObjectivesTo comprehensively identify the metabolic causal factors and potential drug targets for PCOS. MethodsThis genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. ResultsThe PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65–4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17–2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07–1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09–1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47–0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. ConclusionThis study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings.

Causal relationship between serum uric acid levels and male infertility: a bidirectional two-sample Mendelian randomization study

Causal relationship between serum uric acid levels and male infertility: a bidirectional two-sample Mendelian randomization study

Causal relationship between cathepsins and major salivary gland neoplasms: a bidirectional Mendelian randomization study

Causal relationship between cathepsins and major salivary gland neoplasms: a bidirectional Mendelian randomization study

Association between frailty and common psychiatric disorders: A bidirectional Mendelian randomization study

BackgroundThere is growing interest in exploring the relationship between frailty and common psychiatric disorders. However, there have been limited reports on the genetic variation level of frailty with psychiatric disorders. MethodWe conducted large-scale Two-sample Mendelian randomization (MR) analyses to examine whether there is an association between frailty and common psychiatric disorders (bipolar disorder [BD], major depressive disorder [MDD], schizophrenia, and suicide or other Intentional self-harm). We employed multiple MR approaches to conduct the MR analysis, including MR-Egger, weighted median, and random-effect inverse variance weighted (IVW). The IVW method served as the primary analysis. Heterogeneity testing and sensitivity analysis were also conducted in the MR study. ResultsThe MR results denoted that frailty was associated with an increased risk of BD (odds ratio (OR) =1.60, PIVW = 0.017), MDD (OR = 2.04, PIVW < 0.001), schizophrenia (OR = 1.91, PIVW = 0.005), and suicide or other Intentional self-harm (OR = 1.77, PIVW < 0.001). For reverse analysis, we observed no significant association between psychiatric disorders and the risk of frailty. These results remained consistent across sensitivity assessments. ConclusionsOur research indicates a potential unidirectional causal relationship, suggesting that frailty may serve as a risk factor for certain common psychiatric disorders. These findings carry important for implications for psychiatric disorders and frailty patient care.

Exploring Genetic Association of Tea Intake With Allergic Diseases Among European Population: A Bidirectional Mendelian Randomization Study

Exploring Genetic Association of Tea Intake With Allergic Diseases Among European Population: A Bidirectional Mendelian Randomization Study

The impact of anxiety on the risk of kidney stone disease: Insights into eGFR-mediated effects.

Previous studies have linked kidney stone disease (KSD) with depression, but there are no reports on the relationship between anxiety and KSD, and the mechanism underlying the potential relationship remains unclear. Associations of anxiety and incident KSD were assessed in the National Health and Nutrition Examination Survey (NHENES) using multivariate logistic regression. Two-sample bidirectional Mendelian randomization studies and a two-step two-sample MR was used to estimate the mediating factors that influence KSD risk. Examinations of NHANES data revealed that a rise in the frequency and intensity of anxiety were independently associated with incident KSD. In MR analysis, anxiety (uk-a-51 and uk-b-6519) were from the UK Biobank, with sample sizes of 328,717 and 450,765 respectively. KSD data were from the FinnGen, including 8597 cases and 333,128 controls. In the IVW analysis, genetically predicted anxieties (ukb-a-51 and ukb-b-6519) were found to be causally associated with a higher risk of KSD, with odds ratios of 6.18 (95% CI 2.54-15.04) and 3.44 (95% CI 1.67-7.08), respectively. There were no reverse causal effects. Further mediation analysis indicated that anxiety increases the risk of KSD by raising eGFR, through which 11.8% of the effect of anxiety on KSD risk was mediated. The research was confined to individuals of European heritage, and there could be specific genetic variances among diverse ethnicities. The current study suggests anxiety as an independent causal risk factor for KSD and unveils a new pathogenic mechanism, showing that anxiety raises eGFR, thereby increasing the risk of KSD.

Relationship between myocardial infarction and atrial fibrillation: A bidirectional Mendelian randomization study.

Many studies have shown that myocardial infarction (MI) is significantly associated with atrial fibrillation (AF), but the causal relationship between MI and AF has not been established. Therefore, we performed this Mendelian randomization (MR) study to investigate the relationship between MI and AF. We used a publicly available summary statistical dataset for MI based on genome-wide analysis studies (GWAS; ebi-a-GCST011364; 14,825 cases and 2680 controls) and a summary statistical dataset for AF based on an European GWAS (finn-b-I9_AF_REIMB; 10,516 cases and 116,926 controls). The 2-sample bidirectional MR analysis was performed using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods. The causal effect of MI on AF was analyzed using 30 MI-specific single nucleotide polymorphisms (SNPs) that were characterized as instrumental variables (IVs) based on the GWAS data. The causal effect of MI on AF was confirmed by the IVW (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.27-1.58; P < .001), MR-Egger (OR: 1.49; 95% CI: 1.15-1.93; P = .005), and weighted median (OR: 1.42; 95% CI: 1.24-1.63; P < .001) analyses. Furthermore, in the reverse MR analyses, the causal effect of AF on MI was analyzed using 20 AF-specific SNPs that were screened as IVs. The causal effect of AF on MI was significant based on the results from the IVW method (OR: 1.05; 95% CI: 1.00-1.09; P = .033). In conclusion, the bidirectional MR analyses demonstrated a clear bidirectional causal association between MI and AF.

Causal association between non-thyroidal autoimmune diseases and Graves' ophthalmopathy: a mendelian randomization study

PurposeThis Mendelian randomization (MR) analysis study aimed to investigate the genetic causal relationship between non-thyroidal autoimmune diseases (ADs) and Graves' ophthalmopathy (GO). MaterialsSingle nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis vulgaris (PV), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) were obtained from the IEU Open genome-wide association studies (GWAS) database, GWAS data for GO were obtained from the FinnGen database. Bidirectional MR analysis was conducted using inverse variance weighted (IVW) method, weighted median (WM) method and MR-Egger test. Cochran's Q statistic was used to assess the heterogeneity between SNP estimates. MR-Egger regression was used to evaluate horizontal pleiotropy and MR pleiotropy residual sum and outlier (MR-PRESSO) test was used to detect the outliers. ResultsFor non-thyroidal ADs, the forward MR results using the IVM method showed that T1D (OR=1.259, 95%CI 1.026-1.5465; p=0.028) and SLE (OR=1.807, 95%CI 1.229-2.655; p=0.003) were correlated with the risk of GO at the genetic level, while there was no evidence showing that IBD, MS, PV and RA were correlated with GO. In the reverse MR study, there was a significant increase in the risk of developing T1D in GO (OR=1.135, 95%CI 1.018-1.265; p=0.022), but pleiotropy and heterogeneity existed. ConclusionIn the European population, there is strong genetic evidence that patients with T1D and SLE have a higher risk of developing GO, whereas the effect of GO on ADs is unclear.

Correlation between gut microbiota and pancreatitis: a bidirectional Mendelian randomization.

The causative role of gut microbiota in pancreatitis remains unknown. This study aimed to investigate potential causal associations between gut microbiota and pancreatitis, using bidirectional Mendelian randomization (MR) analysis. We analyzed genome-wide association study (GWAS) summary statistics for gut microbiota (211 taxa from gut microbiota, n = 18 340) and two types of pancreatitis, namely acute pancreatitis (AP, 5509 cases and 301 383 controls) and chronic pancreatitis (CP, 3002 cases and 301 383 controls). A reverse MR analysis was also performed to assess the possibility of reverse causation. Nine features (one family + eight genera) showed a causal association with AP. According to inverse-variance weighted (IVW) estimates, phylum Firmicutes (P = 4.10 × 10-2), genus Erysipelatoclostridium (P = 4.80 × 10-2), genus Flavonifractor (P = 4.10 × 10-2), genus Methanobrevibacter (P = 3.40 × 10-2), and genus Prevotella9 (P = 4.60 × 10-2) were found to have a protective effect on AP. Additionally, genus Eubacteriumeligensgroup (P = 4.10 × 10-2), genus Eubacteriumfissicatenagroup (P = 4.00 × 10-3), genus Coprococcus3 (P = 4.10 × 10-2), and genus Haemophilus (P = 4.60 × 10-2) exhibited a positive correlation with AP. Four features (two families + two genera) were causally associated with CP. IVW results also confirmed that family Clostridiaceae1 (P = 3.30 × 10-2), genus LachnospiraceaeFCS020group (P = 4.60 × 10-2), and genus Prevotella9 (P = 1.90 × 10-2) were protective factors for CP, whereas the presence of family Victivallaceae (P = 2.60 × 10-2) correlated with CP risk. No causal effects of pancreatitis (AP or CP) on these gut microbiota taxa were found in the reverse MR analysis. This study confirms a potential causal relationship between gut microbiota and pancreatitis, highlighting the gut microbiota-pancreas axis in the pathogenesis of pancreatitis.

Effect of tea consumption on the development of hypertension, diabetes, and obesity: a bidirectional two-sample Mendelian randomization analysis.

The effect of tea consumption on conditions such as hypertension, diabetes, and obesity has attracted significant global interest. However, the results of various studies on this topic have been mixed and somewhat contentious. Therefore, we conducted a Mendelian randomization (MR) analysis to investigate the causal relationships between tea consumption and the aforementioned health conditions. A bidirectional two-sample MR analysis was used to systematically explores the associations between tea consumption and hypertension, diabetes, and obesity. MR-Egger regression, weighted median, inverse variance weighted, and weighted mode methods were used to evaluate the potential causal associations. Leave-one-out sensitivity test was used to check the robustness of the IVW estimates. MR analysis indicated that genetically predicted tea consumption is associated with a protective effect against hypertension, with an odds ratio (OR) of 0.78 and a 95% confidence interval (CI) ranging from 0.64 to 0.95. Additionally, tea consumption appeared to have a potential protective effect on type 2 diabetes and obesity related to excessive calorie intake, influenced by specific single nucleotide polymorphisms (SNPs), namely "rs57462170" and "rs17685." No causal link was observed between the consumption of green or herbal tea and hypertension, diabetes, or obesity. However, there was a marginal negative association between type 2 diabetes and tea consumption and (OR = 0.99; 95% CI: 0.97-1.00) and a significant negative correlation between obesity due to excessive calorie intake and green tea consumption (OR = 0.35; 95% CI: 0.16-0.78). This study demonstrates a protective causal relationship between the consumption of tea (including black and green teas) and reduced risk of hypertension. Furthermore, our results suggest that tea intake may also have a protective effect on type 2 diabetes and obesity. The results recommend further research to verify or refine these findings.

Bidirectional Mendelian Randomization Analysis of Genetic Proxies of Plasma Fatty Acids and Pre-Eclampsia Risk.

Previous studies have reported associations between fatty acids and the risk of pre-eclampsia. However, the causality of these associations remains uncertain. This study postulates a causal relationship between specific plasma fatty acids and pre-eclampsia or other maternal hypertensive disorders (PE-HTPs). To test this hypothesis, two-sample bidirectional Mendelian randomization (MR) analyses were employed to determine the causality effects. Single-nucleotide polymorphisms associated with PE-HTPs and fatty acids were obtained from a genome-wide association study (GWAS) of European ancestry. Bidirectional MR analyses were conducted using methods such as inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses, including tests for heterogeneity, horizontal pleiotropy, and co-localization, were conducted to assess the robustness of MR results. The analyses revealed causal relationships between PE-HTPs and several fatty acids, including monounsaturated fatty acid (MUFA), omega-6 fatty acid (n-6 FA), linoleic acid (LA), docosahexaenoic acid (DHA), and the PUFA/MUFA ratio. Genetically predicted higher risk of PE-HTPs was significantly associated with lower plasma n-6 FA (OR = 0.96, 95% CI: 0.93-0.99), particularly LA (OR = 0.95, 95% CI: 0.92-0.98). Conversely, increased DHA (OR = 0.86, 95% CI: 0.78-0.96) and a higher PUFA/MUFA ratio (OR = 0.86, 95% CI: 0.76-0.98) were associated with a reduced risk of PE-HTPs. Elevated MUFA levels (OR = 1.12, 95% CI: 1.00-1.25) were related to an increased risk. This study provides robust genetic evidence supporting bidirectional causal relationships between PE-HTPs and specific plasma fatty acids, underscoring the critical role of fatty acid metabolism in maternal hypertensive disorders.

Mendelian randomisation analysis to explore the association between cathepsins and bipolar disorder

IntroductionBipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood.ObjectiveThe aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder.MethodsThe causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis.ResultsIt was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor.ConclusionsIn conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor.

The relationship between immune cells and prostate cancer, and the mediating role of metabolites: a Mendelian randomization study

Research has demonstrated the significant involvement of immune cells in the development and progression of prostate cancer (PCa). However, the precise causal relationship between immune cells and PCa remains unclear. This study utilized bidirectional Mendelian randomization (MR) analysis to investigate the causal link between immune cells and PCa. Additionally, employed mediation MR design to ascertain the potential mediating role of metabolites in the connection between immune cells and PCa outcomes. Unswitched memory B cell % lymphocyte and CD24 + CD27 + B cell % lymphocyte were positively related to PCa risk, while CD62L − monocyte absolute count and CD62L − monocyte % monocyte were negatively associated with PCa risk. Sensitivity analysis was conducted to validate these results. The mediation MR results indicate that 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) levels may be an independent risk factor for PCa, while the succinate to acetoacetate ratio (SA ratio) was found to be a mediator for the effect of CD62L − monocyte % monocyte on PCa, with a mediation proportion of 16.6% (mediation percentage: 16.6%, 95%CI − 163% − 196%). The research validates the genetic causality between particular immune cells and PCa, and has emphasized the potential intermediary function of SA ratio. These noteworthy discoveries provide fresh perspectives for the clinical management of PCa.

Genetical effects of sleep traits on postpartum depression: a bidirectional two-sample Mendelian randomization study

BackgroundPostpartum depression (PPD) is widely recognized as the most prevalent mental health crisis following childbirth and has been linked to sleep disturbances. However, the potential causal relationships between various sleep traits and PPD remain unclear. This study employs a bidirectional two-sample Mendelian randomization (MR) approach to investigate these associations.MethodsThe inverse-variance-weighted method was used to evaluate the causally linked sleep traits on postpartum depression. The weighted median, weighted mode, and MR-Egger were used to estimate the robustness of the inverse-variance-weighted method. The leave-one-out method estimated the sensitivity of the result. Cochran’s Q method was used for the heterogeneous test. The MR-Egger intercept and MR-PRESSO methods detected the horizontal pleiotropy.ResultsWe examined the genetic causal relationships between nine sleep traits and postpartum depression. Sleep apnea syndrome (OR: 1.122; 95%CI: 1.063–1.185; p = 0.000), sleeplessness/insomnia (OR: 1.465; 95%CI: 1.104–1.943; p = 0.008), and frequency of tiredness/lethargy in last 2 weeks (OR: 1.725; 95%CI: 1.345–2.213; p = 0.000) genetically predicted the increased risk of postpartum depression. The reverse Mendelian randomization analysis showed PPD caused sleeplessness/insomnia (β: 0.006; 95%CI: 0.001–0.010; p = 0.016) and frequency of tiredness/lethargy in last 2 weeks (β: 0.007; 95%CI: 0.002–0.011; p = 0.004). The remaining six sleep traits showed no significant association with PPD. There was no heterogeneity or horizontal pleiotropy.ConclusionsGenetic evidence reveals causal relationships between specific sleep traits and PPD, including sleep apnea syndrome, sleeplessness/insomnia, and tiredness. Whether certain sleep health indicators suggest a risk of postpartum depression or sleep issues that are caused by PPD, both may offer insights into the prevention and treatment of PPD.

The causal role of gastroesophageal reflux disease in endometriosis: a bidirectional Mendelian randomization study.

Observational studies have reported an association between gastroesophageal reflux disease (GERD) and endometriosis. We conducted a two-sample and bidirectional Mendelian randomization analysis to determine whether those associations are causal. Two-sample and bidirectional MR analyses were performed using summary statistics from the European Individual Genome-Wide Association Study (GWAS). The inverse variance weighting (IVW) method is used as the main analysis method to evaluate causality. Sensitivity analyses were performed to assess heterogeneity, horizontal versatility, and stability. The results showed no significant causal association between GERD in women with endometriosis in the UK Bank database [ratio (OR) ≈ 0, 95% adjusted interval (CI) 1.0007∼1.0044, P = 0.006] and Finn databases [ratio (OR) = 1.29, 95% adjusted interval (CI) 0.99∼1.67, P = 0.06]. However, when studying the Finn database only for endometriosis, which is confined to the uterus, a significant increase in GERD was limited to the risk of endometriosis in the uterus [ratio (OR) = 1.47, 95% adjusted interval (CI) 1.00∼2.17, P = 0.05]. Sensitivity analysis showed that the results were robust and did not detect multi efficacy or heterogeneity. Meanwhile, reverse MR analysis showed that endometriosis did not increase the risk of GERD. This MR study supports a causal relationship between GERD and an increased risk of endometriosis confined to the uterus. Therefore, patients with gastric esophageal reflux should be treated with gynecological examination to avoid and prevent the development of endometriosis.

Causal relationship between hypothyroidism and ulcerative colitis: a bidirectional Mendelian randomization study.

Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism. We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level. Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways. Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells.