Differential Sleep Traits Have No Causal Effect on Inflammatory Bowel Diseases: A Mendelian Randomization Study

Background: Previous studies suggested an association of sleep disorders with inflammatory bowel disease (IBD) and indicated that using pharmacological treatments for the modulation of circadian rhythms might prevent IBD pathogenesis or aggravation, but whether the effect of sleep traits on IBD was causal is inconclusive and, therefore, prevents drug repurposing based on the previous studies. We aimed to examine the causal effect of different sleep traits on the pathogenesis of IBD.Methods: Genetic instruments for sleep traits were selected from the largest GWAS studies available in the UK Biobank (n = 449,734) and the 23andMe Research (n = 541,333). A two-sample Mendelian randomization (MR) study was conducted to examine the association of the genetic instruments with IBD (12,882 cases and 21,770 controls), ulcerative colitis (6,968 cases, 20,464 controls), and Crohn’s disease (5,956 cases and 14,927 controls). We applied the inverse-variance weighted (IVW) method to estimate causal effects, and we used the weighted median and MR-Egger method for sensitivity analyses.Results: We found that sleep duration (OR, 1.00, 95% CI 1.00–1.01), short sleep duration (OR, 1.07, 95% CI 0.41–2.83), morningness (OR, 1.05, 95% CI 0.87–1.27), daytime napping (OR, 1.64, 95% CI 0.62–4.4), frequent insomnia (OR, 1.17, 95% CI 0.8–1.72), any insomnia (OR, 1.17, 95% CI 0.69–1.97), and snoring (OR, 0.31, 95% CI 0.06–1.54) had no causal effect on IBD, and these sleep traits had no causal effect on ulcerative colitis and Crohn’s disease either. Most of the sensitivity analyses showed consistent results with those of the IVW method.Conclusion: Our MR study did not support the causal effect of sleep traits on IBD. Pharmacological modulation of circadian rhythms for the prevention of IBD pathogenesis was unwarranted.

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Mendelian randomization study of inflammatory bowel disease and bone mineral density

BMC Medicine ◽

10.1186/s12916-020-01778-5 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Fashuai Wu ◽

Yu Huang ◽

Jialu Hu ◽

Zengwu Shao

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Bowel Disease ◽

Mendelian Randomization ◽

Causal Effect ◽

Summary Statistics ◽

Inflammatory Bowel ◽

Randomization Analysis

Abstract Background Recently, the association between inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) and BMD has attracted great interest in the research community. However, the results of the published epidemiological observational studies on the relationship between inflammatory bowel disease and BMD are still inconclusive. Here, we performed a two-sample Mendelian randomization analysis to investigate the causal link between inflammatory bowel disease and level of BMD using publically available GWAS summary statistics. Methods A series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. To make the conclusions more robust and reliable, we utilized several robust analytical methods (inverse-variance weighting, MR-PRESSO method, mode-based estimate method, weighted median, MR-Egger regression, and MR.RAPS method) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, Cochran’s Q test, and “leave-one-out” sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on BMD. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy. Results Our two-sample Mendelian randomization analysis with two groups of exposure GWAS summary statistics and four groups of outcome GWAS summary statistics suggested a definitively causal effect of genetically predicted ulcerative colitis on TB-BMD and FA-BMD but not on FN-BMD or LS-BMD (after Bonferroni correction), and we merely determined a causal effect of Crohn’s disease on FN-BMD but not on the others, which was somewhat inconsistent with many published observational researches. The causal effect of inflammatory bowel disease on TB-BMD was significant and robust but not on FA-BMD, FN-BMD, and LS-BMD, which might result from the cumulative effect of ulcerative colitis and Crohn’s disease on BMDs. Conclusions Our Mendelian randomization analysis supported the causal effect of ulcerative colitis on TB-BMD and FA-BMD. As to Crohn’s disease, only the definitively causal effect of it on decreased FN-BMD was observed. Updated MR analysis is warranted to confirm our findings when a more advanced method to get less biased estimates and better precision or GWAS summary data with more ulcerative colitis and Crohn’s disease patients was available.

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Maternal polycystic ovary syndrome and offspring birth weight: a Mendelian randomization study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab843 ◽

2021 ◽

Author(s):

Yuexin Gan ◽

Donghao Lu ◽

Chonghuai Yan ◽

Jun Zhang ◽

Jian Zhao

Keyword(s):

Birth Weight ◽

Polycystic Ovary Syndrome ◽

Causal Relationship ◽

Mendelian Randomization ◽

Polycystic Ovary ◽

Causal Effect ◽

Sensitivity Analyses ◽

European Ancestry ◽

Ovary Syndrome ◽

Genetic Instruments

Abstract Background Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain. Objective We conducted a two-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW. Methods We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in the genome-wide association study (GWAS) meta-analysis including 10,074 PCOS cases and 103,164 controls of European ancestry from seven cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics (EGG) consortium (n = 406,063 European-ancestry individuals) using the weighted linear model (WLM), an approximation method of structural equation model (SEM), which separated maternal genetic effects from fetal genetic effects. We used a two-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results. Results We found little evidence for a causal effect of maternal PCOS on offspring BW (-6.1 g, 95% confidence interval [CI]: -16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses. Conclusion Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.

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Causal Association Between Birth Weight and Atrial Fibrillation: Evidence from a Two-Sample Mendelian Randomization Analysis

10.21203/rs.3.rs-36815/v1 ◽

2020 ◽

Author(s):

Songzan Chen ◽

Fangkun Yan ◽

Tian Xu ◽

Yao Wang ◽

Kaijie Zhang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Birth Weight ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

P Value ◽

Causal Association ◽

Genome Wide ◽

A Genome ◽

Mr Study

Abstract Background Although several observational studies have shown an association between birth weight (BW) and atrial fibrillation (AF), controversy remains. In this study, we aimed to explore the role of elevated BW on the etiology of AF. Methods A two-sample Mendelian randomization (MR) study was designed to infer the causality. The genetic data on the associations of single nucleotide polymorphisms (SNPs) with BW and AF were separately obtained from two large-scale genome-wide association study with up to 321,223 and 1,030,836 individuals respectively. SNPs were identified at a genome-wide significant level (p-value < 5 × 10− 8). The inverse variance-weighted (IVW) with fixed effects method was performed to obtain causal estimates as our primary analysis. MR-Egger regression was conducted to assess the pleiotropy and sensitivity analyses with various statistical methods were applied to evaluate the robustness of the results. Results In total, 122 SNPs were identified as the genetic instrumental variables. MR analysis revealed a causal effect of elevated BW on AF (OR = 1.21, 95% CI = 1.13–1.29, p-value = 2.39 × 10− 8). The MR-Egger regression suggested no evidence of directional pleiotropy (intercept = 0.00, p-value = 0.62). All the results in sensitivity analyses were consistent with the primary result, which confirmed the causal association between BW and AF. Conclusions The findings from the two-sample MR study indicate a causal effect of elevated BW on AF. This suggests a convenient and effective method to ease the burden of AF by reducing the number of newborns with elevated BW.

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Assessment of Bidirectional Relationships Between Polycystic Ovary Syndrome and Periodontitis: Insights From a Mendelian Randomization Analysis

Frontiers in Genetics ◽

10.3389/fgene.2021.644101 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pengfei Wu ◽

Xinghao Zhang ◽

Ping Zhou ◽

Wan Zhang ◽

Danyang Li ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Odds Ratio ◽

Mendelian Randomization ◽

Polycystic Ovary ◽

Causal Effect ◽

Sensitivity Analyses ◽

Ovary Syndrome ◽

Unit Increase ◽

Log Odds ◽

Mr Study

BackgroundObservational studies have indicated an association between polycystic ovary syndrome (PCOS) and periodontitis, but it is unclear whether the association is cofounded or causal. We conducted a two-sample Mendelian randomization (MR) study to investigate the bidirectional relationship between genetically predicted PCOS and periodontitis.MethodsFrom two genome-wide association studies we selected 13 and 7 single nucleotide polymorphisms associated with PCOS and periodontitis, respectively, as instrumental variables. We utilized publicly shared summary-level statistics from European-ancestry cohorts. To explore the causal effect of PCOS on periodontitis, 12,289 cases of periodontitis and 22,326 controls were incorporated, while 4,890 cases of PCOS and 20,405 controls in the reverse MR. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented.ResultsGenetically determined PCOS was not causally associated with risk of periodontitis (odds ratio 0.97; 95% confidence interval 0.88–1.06; P = 0.50) per one-unit increase in the log-odds ratio of periodontitis. Similarly, no causal effect of periodontitis on PCOS was shown with the odds ratio for PCOS was 1.17 (95% confidence interval 0.91–1.49; P = 0.21) per one-unit increase in the log-odds ratio of periodontitis. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity.ConclusionThe bidirectional MR study couldn’t provide convincing evidence for the causal relationship between genetic liability to PCOS and periodontitis in the Europeans. Triangulating evidence across further observational and genetic-epidemiological studies is necessary.

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Mendelian randomization study shows no causal effects of serum urate levels on the risk of MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000920 ◽

2020 ◽

Vol 8 (1) ◽

pp. e920

Author(s):

Adil Harroud ◽

J. Brent Richards ◽

Sergio E. Baranzini

Keyword(s):

Large Scale ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Serum Urate ◽

Sensitivity Analyses ◽

Data Sets ◽

A Genome ◽

Mr Study

ObjectiveTo examine whether lifelong genetically increased serum urate levels, a potent antioxidant, contribute to MS susceptibility using Mendelian randomization (MR).MethodsThis 2-sample MR study included 25 independent genetic variants strongly associated with serum urate levels in a genome-wide association study meta-analysis of 140,949 individuals. Effects on the risk of MS were assessed with summary statistics from 3 large-scale MS genetic data sets totaling 61,667 MS cases and 86,806 controls from the International MS Genetic Consortium. Multiple sensitivity analyses were performed to evaluate the assumptions of MR and remove potentially pleiotropic variants.ResultsUsing inverse-variance weighted MR, we found no evidence for a causal effect of serum urate level on the risk of MS in any of the cohorts (MS1: OR 0.99 per each mg/dL unit increase in urate, 95% CI 0.89–1.08, p = 0.76; MS2: OR = 0.99, 95% CI 0.89–1.11, p = 0.90; MS3: OR = 1.00, 95% CI 0.98–1.2, p = 0.91). Pleiotropy robust MR methods yielded consistent estimates.ConclusionThis MR study does not support a clinically relevant causal effect of serum urate levels on the risk of MS.

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Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458521993075 ◽

2021 ◽

pp. 135245852199307

Author(s):

Adil Harroud ◽

Ruth Ann Marrie ◽

Kathryn C Fitzgerald ◽

Amber Salter ◽

Yi Lu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mendelian Randomization ◽

Causal Effect ◽

Causal Effects ◽

Sensitivity Analyses ◽

Causal Association ◽

Major Depressive ◽

Genetic Liability ◽

Bidirectional Relationship ◽

Genetic Instruments

Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD ( n = 660,937 cases; 1,453,489 controls) and MS ( n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

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Prebiotics and Probiotics in Inflammatory Bowel Disease: Where are we now and where are we going?

Current Clinical Pharmacology ◽

10.2174/1574884715666200312100237 ◽

2020 ◽

Vol 15 (3) ◽

pp. 216-233 ◽

Cited By ~ 1

Author(s):

Maliha Naseer ◽

Shiva Poola ◽

Syed Ali ◽

Sami Samiullah ◽

Veysel Tahan

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Adverse Effects ◽

Bowel Disease ◽

Relapse Prevention ◽

Remission Induction ◽

Inflammatory Bowel

The incidence, prevalence, and cost of care associated with diagnosis and management of inflammatory bowel disease are on the rise. The role of gut microbiota in the causation of Crohn's disease and ulcerative colitis has not been established yet. Nevertheless, several animal models and human studies point towards the association. Targeting intestinal dysbiosis for remission induction, maintenance, and relapse prevention is an attractive treatment approach with minimal adverse effects. However, the data is still conflicting. The purpose of this article is to provide the most comprehensive and updated review on the utility of prebiotics and probiotics in the management of active Crohn’s disease and ulcerative colitis/pouchitis and their role in the remission induction, maintenance, and relapse prevention. A thorough literature review was performed on PubMed, Ovid Medline, and EMBASE using the terms “prebiotics AND ulcerative colitis”, “probiotics AND ulcerative colitis”, “prebiotics AND Crohn's disease”, “probiotics AND Crohn's disease”, “probiotics AND acute pouchitis”, “probiotics AND chronic pouchitis” and “prebiotics AND pouchitis”. Observational studies and clinical trials conducted on humans and published in the English language were included. A total of 71 clinical trials evaluating the utility of prebiotics and probiotics in the management of inflammatory bowel disease were reviewed and the findings were summarized. Most of these studies on probiotics evaluated lactobacillus, De Simone Formulation or Escherichia coli Nissle 1917 and there is some evidence supporting these agents for induction and maintenance of remission in ulcerative colitis and prevention of pouchitis relapse with minimal adverse effects. The efficacy of prebiotics such as fructooligosaccharides and Plantago ovata seeds in ulcerative colitis are inconclusive and the data regarding the utility of prebiotics in pouchitis is limited. The results of the clinical trials for remission induction and maintenance in active Crohn's disease or post-operative relapse with probiotics and prebiotics are inadequate and not very convincing. Prebiotics and probiotics are safe, effective and have great therapeutic potential. However, better designed clinical trials in the multicenter setting with a large sample and long duration of intervention are needed to identify the specific strain or combination of probiotics and prebiotics which will be more beneficial and effective in patients with inflammatory bowel disease.

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The Changing Prognosis of Ulcerative Colitis and Crohn’s Disease by Decades

Crohn's & Colitis 360 ◽

10.1093/crocol/otab008 ◽

2021 ◽

Author(s):

Burton I Korelitz ◽

Judy Schneider

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Medical Therapy ◽

Bowel Disease ◽

Surgical Intervention ◽

Inflammatory Bowel

Abstract We present a bird’s eye view of the prognosis for both ulcerative colitis and Crohn’s disease as contained in the database of an Inflammatory Bowel Disease gastroenterologist covering the period from 1950 until the present utilizing the variables of medical therapy, surgical intervention, complications and deaths by decades.

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Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02494-4 ◽

2021 ◽

Author(s):

Shuai Yuan ◽

Maria Bruzelius ◽

Susanna C. Larsson

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Mendelian Randomization ◽

Causal Effect ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Increased Risk ◽

Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

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Crohn’s disease and ulcerative colitis patient-reported outcomes signs and symptoms for the remote management of inflammatory bowel disease during the COVID-19 pandemic

Journal of Patient-Reported Outcomes ◽

10.1186/s41687-021-00323-z ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Sergio Pinto ◽

Erica Loddo ◽

Salvatore Paba ◽

Agnese Favale ◽

Fabio Chicco ◽

...

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Bowel Disease ◽

Patient Reported Outcomes ◽

Signs And Symptoms ◽

Patient Reported ◽

Inflammatory Bowel ◽

Active Patients ◽

Active Disease

Abstract Background and aims The COVID-19 pandemic has led to a deep reorganization of hospital services including inflammatory bowel disease (IBD) units. In this situation, conversion of in-person routine follow-up visits into phone consultations might be necessary. Here we explored the feasibility of using the validated Crohn’s Disease (CD) or Ulcerative Colitis (UC) Patient-Reported Outcomes Signs and Symptoms (CD- and UC-PRO/SS) to collect data about abdominal symptoms (abdominal/S) and bowel signs and symptoms (bowel/SS) remotely. Methods CD- and UC-PRO/SS were collected during phone consultations and compared among patients with active and inactive disease. The effectiveness of therapeutic intervention in patients with active disease was assessed by PRO/SS variation. Results Twenty-one CD and 56 UC patients were evaluated by phone. Six (28.6%) CD and 15 (26.8%) UC patients were considered to have active disease. In CD the bowel/SS but not the abdominal/S module was significantly higher in active patients (mean bowel/SS 2.50 [SE ± 0.44] active vs 0.76 [SE ± 0.18] remission, p = 0.008, AUC 0.87; mean abdominal/S 1.11 [SE ± 0.38] active vs 0.24 [SE ± 0.13] remission, p = 0.066). UC-PRO/SS measures were significantly higher in active patients as compared to patients in remission (median bowel/SS 1.63 [SE ± 0.24] active vs 0.33 [SE ± 0.04] remission; p < 0.0001, AUC 0.91; mean abdominal/S 1.03 [SE ± 0.24] vs 0.37 [SE ± 0.12]; p = 0.009, AUC 0.71). Therapy was escalated in 12 patients (3 CD and 9 UC) due to disease relapse. Therapy escalation resulted in the reduction of PRO/SS as evaluated at the subsequent phone consultation. Conclusions PRO/SS might represent a feasible tool to evaluate disease activity and therapy outcome in IBD patients during periods of limited access to outpatient clinics.

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