scholarly journals Evaluating Causal Relationship Between Metabolites and Six Cardiovascular Diseases Based on GWAS Summary Statistics

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahao Qiao ◽  
Meng Zhang ◽  
Ting Wang ◽  
Shuiping Huang ◽  
Ping Zeng
Keyword(s):  
Cardiovascular Diseases ◽  
Causal Relationship ◽  
Metabolic Pathways ◽  
Causal Effect ◽  
Treatment Strategies ◽  
Sensitivity Analyses ◽  
Biological Processes ◽  
Summary Statistics ◽  
False Discovery ◽  
Pathological Mechanism

Cardiovascular diseases (CVDs) remain the main cause of morbidity and mortality worldwide. The pathological mechanism and underlying biological processes of these diseases with metabolites remain unclear. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of metabolites on these diseases by making full use of the latest GWAS summary statistics for 486 metabolites and six major CVDs. Extensive sensitivity analyses were implemented to validate our MR results. We also conducted linkage disequilibrium score regression (LDSC) and colocalization analysis to investigate whether MR findings were driven by genetic similarity or hybridization between LD and disease-associated gene loci. We identified a total of 310 suggestive associations across all metabolites and CVDs, and finally obtained four significant associations, including bradykinin, des-arg(9) (odds ratio [OR] = 1.160, 95% confidence intervals [CIs]: 1.080–1.246, false discovery rate [FDR] = 0.022) on ischemic stroke, N-acetylglycine (OR = 0.946, 95%CIs: 0.920–0.973, FDR = 0.023), X-09026 (OR = 0.845, 95%CIs: 0.779–0.916, FDR = 0.021) and X-14473 (OR = 0.938, 95%CIs = 0.907–0.971, FDR = 0.040) on hypertension. Sensitivity analyses showed that these causal associations were robust, the LDSC and colocalization analyses demonstrated that the identified associations were unlikely confused by LD. Moreover, we identified 15 important metabolic pathways might be involved in the pathogenesis of CVDs. Overall, our work identifies several metabolites that have a causal relationship with CVDs, and improves our understanding of the pathogenesis and treatment strategies for these diseases.

scholarly journals Causal Effects of Life Course Adiposity on Chronic Kidney Disease: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Wanchun Yang ◽  
Hongchun Chen ◽  
Qiuyun Yuan ◽  
Yang Zou
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Life Course ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Body Fat Percentage ◽  
Fat Percentage ◽  
Hip Circumference

Abstract Background Obesity is reported to be tightly correlated the development of chronic kidney disease (CKD). However, whether there exists causation is unknown, and it remains controversial about the role of obesity in CKD is protective or destructive. In this study, we try to infer the causal relationship between life course adiposity and CKD, to provide a rationale for obesity management in CKD patients.Methods A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship of life course adiposity traits including including body mass index (BMI), childhood BMI, body fat percentage (BF), birth weight (BW), waist circumference, hip circumference and waist-to-hip ratio (WHR) to CKD. Significant single nucleotide polymorphisms from genome-wide association study on human adiposity traits were utilized as exposure instruments, and summary statistics of CKD as outcome. The causal relationship was evaluated by inverse variance weighted, MR Egger regression and weighted median methods, and further verified by extensive sensitivity analyses.Results Genetically determined one standard deviation increase in adult BMI was associated with higher risk of CKD in all four MR methods. And other indexes including childhood BMI, body fat percentage, and waist/hip circumference also have a causal effect on the risk of CKD. The results were robust under all sensitivity analyses.Conclusions There exist causal effect of life course adiposity on the risk of CKD. A genetic predisposition to higher adult BMI may increase the risk of CKD.

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

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.

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.

scholarly journals Estimating the causal effect of hearing loss on Alzheimer’s disease: a Mendelian randomisation study

2020 ◽  
Author(s):  
Benjamin M Jacobs ◽  
Alastair J Noyce ◽  
Christopher JD Hardy ◽  
Jason D Warren ◽  
Charles R Marshall
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hearing Loss ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Summary Statistics ◽  
Age Related ◽  
Hearing Difficulty

AbstractBackgroundHearing loss has been identified as one of the most important risk factors for Alzheimer’s disease (AD). However, the causality of this association has not been established.MethodsWe used publicly available GWAS summary statistics to construct instrumental variables for age-related hearing difficulty. We tested these genetic instruments for association with the outcome of AD using AD GWAS summary statistics in a two-sample Mendelian randomisation analysis. We used inverse-variance weighted meta-analysis to estimate the causal effect of hearing-related traits on AD, followed by secondary sensitivity analyses including a mixture of experts approach.ResultsThere was no strong evidence for a causal relationship between genetically-determined hearing difficulty (ORFE-IVW 1.27, 95% CI 0.89 to 1.82, p=0.189) and AD risk. There was no evidence to suggest that unbalanced horizontal pleiotropy was biasing the result. Power calculations indicated our instruments were sufficiently powered to detect the magnitude of effect described in case-control and cohort settings.ConclusionsOur results suggest that the size of the observed relationship between hearing loss and AD cannot be completely accounted for by a direct causal influence. Hearing loss may have more utility as a risk marker for AD than as a modifiable risk factor.

scholarly journals Elucidation of a Causal Relationship Between Platelet Count and Hypertension: A Bi-Directional Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Po-Chun Chiu ◽  
Amrita Chattopadhyay ◽  
Meng-Chun Wu ◽  
Tzu-Hung Hsiao ◽  
Ching-Heng Lin ◽  
...  
Keyword(s):  
Platelet Count ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Exact Nature ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inverse Variance ◽  
Weighted Median

Hypertension has been reported as a major risk factor for diseases such as cardiovascular disease, and associations between platelet activation and risk for hypertension are well-established. However, the exact nature of causality between them remains unclear. In this study, a bi-directional Mendelian randomization (MR) analysis was conducted on 15,996 healthy Taiwanese individuals aged between 30 and 70 years from the Taiwan Biobank, recorded between 2008 and 2015. The inverse variance weighted (IVW) method was applied to determine the causal relationship between platelet count and hypertension with single nucleotide polymorphisms as instrumental variables (IVs). Furthermore, to check for pleiotropy and validity of the IVs, sensitivity analyses were performed using the MR-Egger, weighted median and simple median methods. This study provided evidence in support of a positive causal effect of platelet count on the risk of hypertension (odds ratio: 1.149, 95% confidence interval: 1.131–1.578, P < 0.05), using the weighted median method. A significant causal effect of platelet count on hypertension was observed using the IVW method. No pleiotropy was observed. The causal effect of hypertension on platelet count was found to be non-significant. Therefore, the findings from this study provide evidence that higher platelet count may have a significant causal effect on the elevated risk of hypertension for the general population of Taiwan.

scholarly journals Cannabis Use and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Jianqiang Zhao ◽  
Heng Chen ◽  
Chengui Zhuo ◽  
Shudong Xia
Keyword(s):  
Body Mass Index ◽  
Cardiovascular Diseases ◽  
Body Mass ◽  
Tobacco Use ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cannabis Use ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genetically Determined

Several observational studies have shown that cannabis use has negative effects on the cardiovascular system, but the causality of this relationship has not been confirmed. The aim of the current study was to estimate the effects of genetically determined cannabis use on risk of cardiovascular diseases. Ten single-nucleotide polymorphisms related to cannabis use were employed as instruments to estimate the association between genetically determined cannabis use and risk of cardiovascular diseases using a two-sample Mendelian randomization (MR) method. Summary statistics data on exposure and outcomes were obtained from different genome-wide association meta-analysis studies. The results of this MR analysis showed no causal effects of cannabis use on the risk of several common cardiovascular diseases, including coronary artery disease, myocardial infarction, stroke and ischemic stroke subtypes, atrial fibrillation (AF), and heart failure. Various sensitivity analyses yielded similar results, and no heterogeneity and directional pleiotropy were observed. After adjusting for tobacco use and body mass index, multivariable MR analysis suggested a causal effect of cannabis use on small vessel stroke (SVS) [odds ratio (OR) 1.17; 95% CI 1.02–1.35; p = 0.03] and AF (OR 1.06; 95% CI 1.01–1.10; p = 0.01), respectively. This two-sample MR study did not demonstrate a causal effect of genetic predisposition to cannabis use on several common cardiovascular outcomes. After adjusting for tobacco use and body mass index, the multivariable MR analysis suggested a detrimental effect of cannabis use on the risk of SVS and AF, respectively.

scholarly journals The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Huang ◽  
Yuqing Hou ◽  
Yixin Zou ◽  
Xiangyu Ye ◽  
Rongbin Yu ◽  
...  
Keyword(s):  
Causal Relationship ◽  
Thyroid Dysfunction ◽  
Mendelian Randomization ◽  
Causal Relation ◽  
Causal Effect ◽  
Thyroid Stimulating Hormone ◽  
Sensitivity Analyses ◽  
Reverse Direction ◽  
Primary Biliary Cholangitis ◽  
Autoimmune Thyroid

Background: Primary biliary cholangitis (PBC) is an autoimmune disease and is often accompanied by thyroid dysfunction. Understanding the potential causal relationship between PBC and thyroid dysfunction is helpful to explore the pathogenesis of PBC and to develop strategies for the prevention and treatment of PBC and its complications.Methods: We used a two-sample Mendelian randomization (MR) method to estimate the potential causal effect of PBC on the risk of autoimmune thyroid disease (AITD), thyroid-stimulating hormone (TSH) and free thyroxine (FT4), hyperthyroidism, hypothyroidism, and thyroid cancer (TC) in the European population. We collected seven datasets of PBC and related traits to perform a series MR analysis and performed extensive sensitivity analyses to ensure the reliability of our results.Results: Using a sensitivity analysis, we found that PBC was a risk factor for AITD, TSH, hypothyroidism, and TC with odds ratio (OR) of 1.002 (95% CI: 1.000–1.005, p = 0.042), 1.016 (95% CI: 1.006–1.027, p = 0.002), 1.068 (95% CI: 1.022–1.115, p = 0.003), and 1.106 (95% CI: 1.019–1.120, p = 0.042), respectively. Interestingly, using reverse-direction MR analysis, we also found that AITD had a significant potential causal association with PBC with an OR of 0.021 (p = 5.10E−4) and that the other two had no significant causal relation on PBC.Conclusion: PBC causes thyroid dysfunction, specifically as AITD, mild hypothyroidism, and TC. The potential causal relationship between PBC and thyroid dysfunction provides a new direction for the etiology of PBC.

scholarly journals The Causal Effects of Insomnia on Bipolar Disorder, Depression, and Schizophrenia: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Huang ◽  
Yixin Zou ◽  
Xingyu Zhang ◽  
Xiangyu Ye ◽  
Yidi Wang ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Psychiatric Disorder ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Treatment Strategies ◽  
European Population ◽  
Sensitivity Analyses ◽  
Causal Mechanism ◽  
Assumption Violations

Psychiatric disorder, including bipolar disorder (BD), major depression (MDD), and schizophrenia (SCZ), affects millions of persons around the world. Understanding the disease causal mechanism underlying the three diseases and identifying the modifiable risk factors for them hold the key for the development of effective preventative and treatment strategies. We used a two-sample Mendelian randomization method to assess the causal effect of insomnia on the risk of BD, MDD, and SCZ in a European population. We collected one dataset of insomnia, three of BD, one of MDD, and three of SCZ and performed a meta-analysis for each trait, further verifying the analysis through extensive complementarity and sensitivity analysis. Among the three psychiatric disorders, we found that only insomnia is causally associated with MDD and that higher insomnia increases the risk of MDD. Specifically, the odds ratio of MDD increase of insomnia is estimated to be 1.408 [95% confidence interval (CI): 1.210–1.640, p = 1.03E-05] in the European population. The identified causal relationship between insomnia and MDD is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our results provide new evidence to support the causal effect of insomnia on MDD and pave ways for reducing the psychiatric disorder burden.

scholarly journals Preharvest UV-C Hormesis Induces Key Genes Associated With Homeostasis, Growth and Defense in Lettuce Inoculated With Xanthomonas campestris pv. vitians

2022 ◽  
Vol 12 ◽  
Author(s):  
Amadou Sidibé ◽  
Marie Thérèse Charles ◽  
Jean-François Lucier ◽  
Yanqun Xu ◽  
Carole Beaulieu
Keyword(s):  
Metabolic Pathways ◽  
Xanthomonas Campestris ◽  
Virulent Strain ◽  
Normal Growth ◽  
Biological Processes ◽  
Beneficial Effects ◽  
Physiological Processes ◽  
False Discovery ◽  
Ultraviolet C ◽  
Uv C

Preharvest application of hormetic doses of ultraviolet-C (UV-C) generates beneficial effects in plants. In this study, within 1 week, four UV-C treatments of 0.4 kJ/m2 were applied to 3-week-old lettuce seedlings. The leaves were inoculated with a virulent strain of Xanthomonas campestris pv. vitians (Xcv) 48 h after the last UV-C application. The extent of the disease was tracked over time and a transcriptomic analysis was performed on lettuce leaf samples. Samples of lettuce leaves, from both control and treated groups, were taken at two different times corresponding to T2, 48 h after the last UV-C treatment and T3, 24 h after inoculation (i.e., 72 h after the last UV-C treatment). A significant decrease in disease severity between the UV-C treated lettuce and the control was observed on days 4, 8, and 14 after pathogen inoculation. Data from the transcriptomic study revealed, that in response to the effect of UV-C alone and/or UV-C + Xcv, a total of 3828 genes were differentially regulated with fold change (|log2-FC|) > 1.5 and false discovery rate (FDR) < 0.05. Among these, of the 2270 genes of known function 1556 were upregulated and 714 were downregulated. A total of 10 candidate genes were verified by qPCR and were generally consistent with the transcriptomic results. The differentially expressed genes observed in lettuce under the conditions of the present study were associated with 14 different biological processes in the plant. These genes are involved in a series of metabolic pathways associated with the ability of lettuce treated with hormetic doses of UV-C to resume normal growth and to defend themselves against potential stressors. The results indicate that the hormetic dose of UV-C applied preharvest on lettuce in this study, can be considered as an eustress that does not interfere with the ability of the treated plants to carry on a set of key physiological processes namely: homeostasis, growth and defense.

scholarly journals Effect Estimates in Randomized Trials and Observational Studies: Comparing Apples With Apples

2019 ◽  
Vol 188 (8) ◽  
pp. 1569-1577 ◽  
Author(s):  
Sara Lodi ◽  
Andrew Phillips ◽  
Jens Lundgren ◽  
Roger Logan ◽  
Shweta Sharma ◽  
...  
Keyword(s):  
Data Analysis ◽  
Antiretroviral Therapy ◽  
Observational Studies ◽  
Randomized Trials ◽  
Causal Effect ◽  
Treatment Strategies ◽  
Sensitivity Analyses ◽  
Eligibility Criteria ◽  
Study Protocols ◽  
The Impact

Abstract Effect estimates from randomized trials and observational studies might not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a 3-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocols (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate our approach, we compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive for the human immunodeficiency virus from the Strategic Timing of Antiretroviral Therapy (START) randomized trial and the observational HIV-CAUSAL Collaboration.

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