scholarly journals Association between genetically elevated levels of inflammatory biomarkers and risk of schizophrenia: a two-sample Mendelian randomisation study

2017 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Maria Carolina Borges ◽  
Bernardo Lessa Horta ◽  
Jack Bowden ◽  
George Davey Smith
Keyword(s):  
Odds Ratio ◽  
Observational Studies ◽  
Causal Effect ◽  
Interleukin 1 ◽  
Inflammatory Biomarkers ◽  
Mendelian Randomisation ◽  
Reactive Protein ◽  
Odds Ratio Estimate ◽  
Interleukin 6 Receptor ◽  
Residual Confounding

AbstractBackgroundPositive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias such as reverse causation and residual confounding.MethodsIn this study, we used summary data to evaluate the association of genetically elevated C reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra) and soluble interleukin-6 receptor (IL-6R) levels with schizophrenia in a two-sample Mendelian randomisation design.ResultsThe pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (95% CI: 0.84; 0.97) per two-fold increment in CRP levels; consistent results were obtained using different Mendelian randomisation methods and a more conservative set of instruments. The odds ratio for soluble IL-6R was 1.06 (95% CI: 1.01; 1.12) per two-fold increment. Estimates for IL-1Ra were inconsistent among instruments and pooled estimates were imprecise and centred on the null.ConclusionUnder Mendelian randomisation assumptions, our findings suggest a protective causal effect of CRP and a risk-increasing causal effect of soluble IL-6R (potentially mediated at least in part by CRP) on schizophrenia risk.

scholarly journals Examining the effect of smoking on suicidal ideation and attempts: triangulation of epidemiological approaches

2020 ◽  
Vol 217 (6) ◽  
pp. 701-707 ◽  
Author(s):  
Ruth Harrison ◽  
Marcus R. Munafò ◽  
George Davey Smith ◽  
Robyn E. Wootton
Keyword(s):  
Suicidal Ideation ◽  
Odds Ratio ◽  
Suicide Attempts ◽  
Causal Effect ◽  
Smoking Status ◽  
Strong Association ◽  
Mendelian Randomisation ◽  
Polymorphism Analysis ◽  
Suicidal Thoughts ◽  
Smoking Behaviours

BackgroundPrevious literature has demonstrated a strong association between cigarette smoking, suicidal ideation and suicide attempts. This association has not previously been examined in a causal inference framework and could have important implications for suicide prevention strategies.AimsWe aimed to examine the evidence for an association between smoking behaviours (initiation, smoking status, heaviness, lifetime smoking) and suicidal thoughts or attempts by triangulating across observational and Mendelian randomisation analyses.MethodFirst, in the UK Biobank, we calculated observed associations between smoking behaviours and suicidal thoughts or attempts. Second, we used Mendelian randomisation to explore the relationship between smoking and suicide attempts and ideation, using genetic variants as instruments to reduce bias from residual confounding and reverse causation.ResultsOur observational analysis showed a relationship between smoking behaviour, suicidal ideation and attempts, particularly between smoking initiation and suicide attempts (odds ratio, 2.07; 95% CI 1.91–2.26; P < 0.001). The Mendelian randomisation analysis and single-nucleotide polymorphism analysis, however, did not support this (odds ratio for lifetime smoking on suicidal ideation, 0.050; 95% CI −0.027 to 0.127; odds ratio on suicide attempts, 0.053; 95% CI, −0.003 to 0.110). Despite past literature showing a positive dose-response relationship, our results showed no clear evidence for a causal effect of smoking on suicidal ideation or attempts.ConclusionsThis was the first Mendelian randomisation study to explore the effect of smoking on suicidal ideation and attempts. Our results suggest that, despite observed associations, there is no clear evidence for a causal effect.

scholarly journals Tendency towards being a “Morning person” increases risk of Parkinson’s disease: evidence from Mendelian randomisation

2018 ◽  
Author(s):  
AJ Noyce ◽  
DA Kia ◽  
K Heilbron ◽  
JEC Jepson ◽  
G Hemani ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Circadian Rhythm ◽  
Causal Relationship ◽  
Odds Ratio ◽  
Causal Effect ◽  
Coffee Consumption ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Effect Estimate

AbstractBackgroundCircadian rhythm may play a role in neurodegenerative diseases such as Parkinson’s disease (PD). Chronotype is the behavioural manifestation of circadian rhythm and Mendelian randomisation (MR) involves the use of genetic variants to explore causal effects of exposures on outcomes. This study aimed to explore a causal relationship between chronotype and coffee consumption on risk of PD.MethodsTwo-sample MR was undertaken using publicly available GWAS data. Associations between genetic instrumental variables (IV) and “morning person” (one extreme of chronotype) were obtained from the personal genetics company 23andMe, Inc., and UK Biobank, and consisted of the per-allele odds ratio of being a “morning person” for 15 independent variants. The per-allele difference in log-odds of PD for each variant was estimated from a recent meta-analysis. The inverse variance weight method was used to estimate an odds ratio (OR) for the effect of being a “morning person” on PD. Additional MR methods were used to check for bias in the IVW estimate, arising through violation of MR assumptions. The results were compared to analyses employing a genetic instrument of coffee consumption, because coffee consumption has been previously inversely linked to PD.FindingsBeing a “morning person” was causally linked with risk of PD (OR 1⋅27; 95% confidence interval 1⋅06-1⋅51; p=0⋅012). Sensitivity analyses did not suggest that invalid instruments were biasing the effect estimate and there was no evidence for a reverse causal relationship between liability for PD and chronotype. There was no robust evidence for a causal effect of high coffee consumption using IV analysis, but the effect was imprecisely estimated (OR 1⋅12; 95% CI 0⋅89-1⋅42; p=0⋅22).InterpretationWe observed causal evidence to support the notion that being a “morning person”, a phenotype driven by the circadian clock, is associated with a higher risk of PD. Further work on the mechanisms is warranted and may lead to novel therapeutic targets.FundingNo specific funding source.

Impact of data extraction errors in meta-analyses on the association between depression and peripheral inflammatory biomarkers: an umbrella review

2021 ◽  
pp. 1-14
Author(s):  
San Lee ◽  
Keum Hwa Lee ◽  
Kyung Mee Park ◽  
Sung Jong Park ◽  
Won Jae Kim ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Data Extraction ◽  
Interleukin 1 ◽  
Inflammatory Biomarkers ◽  
Cochrane Library ◽  
Calculation Error ◽  
Insufficient Data ◽  
Sample Sizes ◽  
Reactive Protein ◽  
Meta Analyses

Abstract Background Accumulating evidence suggests that alterations in inflammatory biomarkers are important in depression. However, previous meta-analyses disagree on these associations, and errors in data extraction may account for these discrepancies. Methods PubMed/MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from database inception to 14 January 2020. Meta-analyses of observational studies examining the association between depression and levels of tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), interleukin-6 (IL-6), and C-reactive protein (CRP) were eligible. Errors were classified as follows: incorrect sample sizes, incorrectly used standard deviation, incorrect participant inclusion, calculation error, or analysis with insufficient data. We determined their impact on the results after correction thereof. Results Errors were noted in 14 of the 15 meta-analyses included. Across 521 primary studies, 118 (22.6%) showed the following errors: incorrect sample sizes (20 studies, 16.9%), incorrect use of standard deviation (35 studies, 29.7%), incorrect participant inclusion (7 studies, 5.9%), calculation errors (33 studies, 28.0%), and analysis with insufficient data (23 studies, 19.5%). After correcting these errors, 11 (29.7%) out of 37 pooled effect sizes changed by a magnitude of more than 0.1, ranging from 0.11 to 1.15. The updated meta-analyses showed that elevated levels of TNF- α, IL-6, CRP, but not IL-1β, are associated with depression. Conclusions These findings show that data extraction errors in meta-analyses can impact findings. Efforts to reduce such errors are important in studies of the association between depression and peripheral inflammatory biomarkers, for which high heterogeneity and conflicting results have been continuously reported.

scholarly journals Elevated C-reactive protein and late-onset bipolar disorder in 78 809 individuals from the general population

2016 ◽  
Vol 208 (2) ◽  
pp. 138-145 ◽  
Author(s):  
Marie Kim Wium-Andersen ◽  
David Dynnes Ørsted ◽  
Børge Grønne Nordestgaard
Keyword(s):  
Bipolar Disorder ◽  
General Population ◽  
Odds Ratio ◽  
Late Onset ◽  
Mendelian Randomisation ◽  
C Reactive Protein ◽  
Cross Sectional ◽  
Reactive Protein ◽  
Continuous Scale ◽  
Increased Risk

BackgroundNo prospective studies have examined the role of C-reactive protein (CRP) in late-onset bipolar disorder.AimsWe tested the hypothesis that elevated levels of CRP are associated cross-sectionally and prospectively with late-onset bipolar disorder, and that such an association possibly is causal.MethodWe performed cross-sectional and prospective analyses with a median follow-up time of 5.9 years (interquartile range: 4.4– 7.6) in 78 809 individuals from the general population, and used genetic variants influencing CRP levels to perform a Mendelian randomisation study.ResultsElevated levels of CRP were associated both cross-sectionally and prospectively with late-onset bipolar disorder. When CRP was on a continuous scale, a doubling in CRP yielded an observational odds ratio for late-onset bipolar disorder of 1.28 (1.08–1.52) with a corresponding causal odds ratio of 4.66 (0.89–24.3).ConclusionElevated CRP is associated with increased risk of late-onset bipolar disorder in the general population which was supported by the genetic analysis.

scholarly journals Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa

2020 ◽  
Author(s):  
Danielle M. Adams ◽  
William R. Reay ◽  
Michael P. Geaghan ◽  
Murray J. Cairns
Keyword(s):  
Anorexia Nervosa ◽  
Psychiatric Disorders ◽  
Observational Studies ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Fasting Insulin ◽  
Multiple Testing Correction ◽  
Insulin Levels ◽  
Glycaemic Traits ◽  
The Relationship

Abstract Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore, causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a natural log transformed pmol/L increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71]—inverse-variance weighted estimate). There was no consistently strong evidence for a causal effect of glycaemic factors on the other seven psychiatric disorders considered. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.

scholarly journals Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis

2021 ◽  
Author(s):  
Richard Culliford ◽  
Alex J. Cornish ◽  
Philip J. Law ◽  
Susan M. Farrington ◽  
Kimmo Palin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Large Scale ◽  
Causal Effect ◽  
Gallstone Disease ◽  
Epidemiological Studies ◽  
Mendelian Randomisation ◽  
Linear Relationships ◽  
Potential Risk Factors ◽  
The Relationship ◽  
Circulating Levels

Abstract Background Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). Methods We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. Results No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96–1.03, P value = 0.90) with CRC was shown. Conclusions Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

scholarly journals Osteoarthritis: Insights Offered by the Study of Bone Mass Genetics

2021 ◽  
Vol 19 (2) ◽  
pp. 115-122
Author(s):  
A. Hartley ◽  
C. L. Gregson ◽  
L. Paternoster ◽  
J. H. Tobias
Keyword(s):  
Bone Mass ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Mineral Density ◽  
High Bone Mass ◽  
Increased Risk ◽  
High Bone ◽  
Genetic Mechanisms ◽  
Additional Support

Abstract Purpose of Review This paper reviews how bone genetics has contributed to our understanding of the pathogenesis of osteoarthritis. As well as identifying specific genetic mechanisms involved in osteoporosis which also contribute to osteoarthritis, we review whether bone mineral density (BMD) plays a causal role in OA development. Recent Findings We examined whether those genetically predisposed to elevated BMD are at increased risk of developing OA, using our high bone mass (HBM) cohort. HBM individuals were found to have a greater prevalence of OA compared with family controls and greater development of radiographic features of OA over 8 years, with predominantly osteophytic OA. Initial Mendelian randomisation analysis provided additional support for a causal effect of increased BMD on increased OA risk. In contrast, more recent investigation estimates this relationship to be bi-directional. However, both these findings could be explained instead by shared biological pathways. Summary Pathways which contribute to BMD appear to play an important role in OA development, likely reflecting shared common mechanisms as opposed to a causal effect of raised BMD on OA. Studies in HBM individuals suggest this reflects an important role of mechanisms involved in bone formation in OA development; however further work is required to establish whether the same applies to more common forms of OA within the general population.

scholarly journals Inflammatory Biomarkers in the Short-Term Prognosis of Venous Thromboembolism: A Narrative Review

2021 ◽  
Vol 22 (5) ◽  
pp. 2627
Author(s):  
Francisco Galeano-Valle ◽  
Lucía Ordieres-Ortega ◽  
Crhistian Mario Oblitas ◽  
Jorge del-Toro-Cervera ◽  
Luis Alvarez-Sala-Walther ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Risk Stratification ◽  
Hemodynamic Instability ◽  
Inflammatory Biomarkers ◽  
Right Ventricle Dysfunction ◽  
Reactive Protein ◽  
Cancer Associated Thrombosis ◽  
The Relationship ◽  
Acute Pe

The relationship between inflammation and venous thrombosis is not well understood. An inflammatory response may be both the cause and consequence of venous thromboembolism (VTE). In fact, several risk factors of VTE modulate thrombosis through inflammatory markers. Acute pulmonary embolism (PE) is burdened by a remarkable mortality rate, up to 34% in severely ill patients presenting with hemodynamic instability. Initial mortality risk stratification is based on hemodynamic instability. Patients with a situation of hemodynamic stability require immediate further risk assessment based on clinical, imaging, and circulating biomarkers, as well as the presence of comorbidities. Some inflammatory biomarkers have shown potential usefulness in the risk stratification of patients with VTE, especially acute PE. C-reactive protein on admission is associated with 30-day mortality and bleeding in VTE patients. P-selectin is associated with right ventricle dysfunction in PE patients and might be associated with VTE recurrences and the extension of thrombosis. Tissue factor microparticles are associated with VTE recurrence in cancer-associated thrombosis. Other inflammatory biomarkers present scarce evidence (inflammatory cytokines, erythrocyte sedimentation rate, fibrinogen, leukocyte count). In this manuscript, we will review the prognostic role of different inflammatory biomarkers available both for clinical practice and research in VTE patients.

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