scholarly journals Alcohol intake and hypertensive disorders of pregnancy: a negative control analysis in the ALSPAC cohort

2021 ◽  
Author(s):  
Florence Z Martin ◽  
Abigail Fraser ◽  
Luisa Zuccolo
Keyword(s):  
Alcohol Intake ◽  
Causal Effect ◽  
Negative Control ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Control Analysis ◽  
Inverse Association ◽  
Hypertensive Disorders Of Pregnancy ◽  
Beverage Type ◽  
Hypertensive Disorders

AbstractIntroductionAlcohol intake increases blood pressure, yet estimates of associations between maternal intake and hypertensive disorders of pregnancy (HDP) are sparse and range from null to a protective effect. Here we estimated the association of maternal drinking during pregnancy with preeclampsia and gestational hypertension (separately and jointly, as HDP). We used partner’s alcohol intake as a negative control exposure, beverage type-specific models, and a range of sensitivity analyses to strengthen causal inference and reduce the influence of bias.MethodsWe performed a prospective cohort study using data on self-reported alcohol intake in the UK Avon Longitudinal Study of Parents And Children (ALSPAC) and HDP ascertained from obstetric notes. Multivariable multinomial regression models were adjusted for confounders and mutually adjusted for partner’s or maternal alcohol intake in the negative control analysis. We also performed a beverage type analysis of the effect of beer and wine separately on HDP risk, due to different social patterning associated with different drinks. Sensitivity analyses assessed the robustness of results to assumptions of no recall bias, no residual confounding, and no selection bias.ResultsOf the 8,999 women eligible for inclusion, 1,490 developed HDP (17%). Both maternal and partner’s drinking were associated with decreased HDP odds (mutually adjusted odds ratio 0.86, 95% confidence interval 0.77 to 0.96, P-value=0.008 and 0.82, 0.70 to 0.97, P=0.018, respectively). We demonstrate the validity of the negative control analyses using the same approach for smoking as the exposure. This confirmed an inverse association for maternal but not partner’s smoking, as expected. Estimates were more extreme for increasing levels of wine intake compared to increasing levels of beer. Multiple sensitivity analyses did not alter our conclusions.ConclusionWe observed an inverse relationship between alcohol intake during pregnancy and risk of HDP for both maternal and, more surprisingly, partner’s drinking. We speculate that this is more likely to be due to common environmental exposures shared between pregnant women and their partners, rather than a true causal effect. This warrants further investigation using different study designs, including Mendelian randomisation.

scholarly journals 1241Alcohol and hypertensive disorders of pregnancy: a negative control analysis

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Flo Martin ◽  
Abigail Fraser ◽  
Luisa Zuccolo
Keyword(s):  
Alcohol Intake ◽  
Gestational Hypertension ◽  
Negative Control ◽  
Sensitivity Analyses ◽  
Control Analysis ◽  
Hypertensive Disorders Of Pregnancy ◽  
Multinomial Regression ◽  
Alcohol Sensitivity ◽  
Hypertensive Disorders ◽  
Parents And Children

Abstract Background Alcohol increases blood pressure, yet estimates of its association with pre-eclampsia range from positive to negative. Here we estimated the association of maternal drinking during pregnancy with preeclampsia and gestational hypertension, separately and jointly as hypertensive disorders of pregnancy (HDP). We also used partner’s alcohol intake as a negative control exposure to strengthen causal inference. Methods We used data on self-reported alcohol intake in the Avon Longitudinal Study of Parents And Children (ALSPAC, N∼9,000). HDP was ascertained from obstetric notes. Multivariable multinomial regression models were adjusted for confounders and mutually-adjusted for partner’s or maternal alcohol. Sensitivity analyses assessed the robustness of results to assumptions of no selection bias, no reporting bias, and no residual confounding (e.g. comparing estimates for beer and wine separately, which have different socioeconomic patterning). Results In mutually-adjusted analyses, maternal and partner’s drinking were associated with decreased HDP odds (OR(95% CI): 0.86(0.77–0.96) and 0.82(0.70-0.97)) respectively. In contrast, the negative control design confirmed the expected associations for maternal but not partner’s smoking (figure), demonstrating the validity of this approach. Multiple sensitivity analyses did not alter results. Estimates were more extreme for increasing levels of wine compared to increasing levels of beer drinking. Conclusions Our extensive negative control and sensitivity analyses point at confounding mechanisms shared between mothers and partners as the most plausible explanation for the alcohol-HDP association. Key messages It is unlikely that alcohol intake in pregnancy reduces the risk of HDP.

scholarly journals Does smoking cause lower educational attainment and general cognitive ability? Triangulation of causal evidence using multiple study designs

2020 ◽  
pp. 1-9
Author(s):  
Suzanne H. Gage ◽  
Hannah M. Sallis ◽  
Glenda Lassi ◽  
Robyn E. Wootton ◽  
Claire Mokrysz ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Cognitive Ability ◽  
Fluid Intelligence ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
General Cognitive Ability ◽  
Inverse Variance ◽  
Lower Educational Attainment

Abstract Background Observational studies have found associations between smoking and both poorer cognitive ability and lower educational attainment; however, evaluating causality is challenging. We used two complementary methods to explore this. Methods We conducted observational analyses of up to 12 004 participants in a cohort study (Study One) and Mendelian randomisation (MR) analyses using summary and cohort data (Study Two). Outcome measures were cognitive ability at age 15 and educational attainment at age 16 (Study One), and educational attainment and fluid intelligence (Study Two). Results Study One: heaviness of smoking at age 15 was associated with lower cognitive ability at age 15 and lower educational attainment at age 16. Adjustment for potential confounders partially attenuated findings (e.g. fully adjusted cognitive ability β −0.736, 95% CI −1.238 to −0.233, p = 0.004; fully adjusted educational attainment β −1.254, 95% CI −1.597 to −0.911, p < 0.001). Study Two: MR indicated that both smoking initiation and lifetime smoking predict lower educational attainment (e.g. smoking initiation to educational attainment inverse-variance weighted MR β −0.197, 95% CI −0.223 to −0.171, p = 1.78 × 10−49). Educational attainment results were robust to sensitivity analyses, while analyses of general cognitive ability were less so. Conclusion We find some evidence of a causal effect of smoking on lower educational attainment, but not cognitive ability. Triangulation of evidence across observational and MR methods is a strength, but the genetic variants associated with smoking initiation may be pleiotropic, suggesting caution in interpreting these results. The nature of this pleiotropy warrants further study.

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 Genetically determined circulating levels ofcytokines and the risk of rheumatoid arthritis

2020 ◽  
Author(s):  
Yu Qian ◽  
Zhixing He ◽  
Sizheng Steven Zhao ◽  
Bin Liu ◽  
Ying Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Observational Studies ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Effect Estimate ◽  
Inverse Association ◽  
A Genome ◽  
Genetically Determined ◽  
Circulating Levels

Abstract Background: Accumulation of inflammatory leukocytes in articular tissues is the hallmark feature of rheumatoid arthritis (RA). Increasing evidence from observational studies have suggested that several cytokines are relevant in the disease process of RA. However, traditional observational studies are susceptible to bias from confounding and reverse causation; therefore, the potential causal association of individual cytokines with the risk of RA remains elusive. Our study aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of RA by conducting a two-sample Mendelian randomization (MR) study.Methods: We identified single nucleotide polymorphisms (SNPs) associated with circulating levels of cytokines and growth factors from a genome-wide association study (GWAS) including 8,293 participants of European ancestry as instrumental variables (IVs). The association estimates of these IVs with RA were obtained from a GWAS meta-analysis including 14,361 RA cases and 43,923 controls of European ancestry. MR analyses were performed using the random-effects inverse variance-weighted, weighted-median, MR-Egger and MR pleiotropy residual sum and outlier tests. Sensitivity analyses were further performed using restricted IVs excluding potential pleiotropic SNPs.Results: In the primary MR analysis, a total of 270 SNPs associated with circulating levels of 27 cytokines were identified and used as IVs. We found a suggestive inverse association between genetically determined circulating level of macrophage inflammatory protein-1β (MIP-1b) and the risk of RA [odds ratio (OR): 0.97, 95% confidence interval (CI) = 0.92-0.99, P = 0.016]. The association remained statistically significant in alternative MR analyses, and the causal effect estimate from sensitivity analysis using the restricted IVs was similar.Conclusions: Genetically determined elevated circulating level of MIP-1b was associated with a lower risk of RA. Further studies are warranted to determine how this MIP-1b and related pathways contribute to the development of RA.

scholarly journals Mendelian randomisation study of smoking exposure in relation to breast cancer risk

2021 ◽  
Author(s):  
Hanla A. Park ◽  
Sonja Neumeyer ◽  
Kyriaki Michailidou ◽  
Manjeet K. Bolla ◽  
Qin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Smoking Exposure

Abstract Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

Alcohol intake and the risk of intracerebral hemorrhage in the elderly

Neurology ◽  
2018 ◽  
Vol 91 (3) ◽  
pp. e227-e235 ◽  
Author(s):  
Paolo Costa ◽  
Mario Grassi ◽  
Licia Iacoviello ◽  
Marialuisa Zedde ◽  
Simona Marcheselli ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Alcohol Intake ◽  
Causal Effect ◽  
Cerebral Haemorrhage ◽  
The Elderly ◽  
Directed Acyclic Graphs ◽  
Control Analysis ◽  
Acyclic Graphs ◽  
Back Door ◽  
Case Control Analysis

ObjectiveTo investigate the role of alcohol as a causal factor for intracerebral hemorrhage (ICH) and whether its effects might vary according to the pathogenic mechanisms underlying cerebral bleeding.MethodsWe performed a case-control analysis, comparing a cohort of consecutive white patients with ICH aged 55 years and older with a group of age- and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy) between 2002 and 2014. Participants were dichotomized into excessive drinkers (>45 g of alcohol) and light to moderate drinkers or nondrinkers. To isolate the unconfounded effect of alcohol on ICH, we used causal directed acyclic graphs and the back-door criterion to select a minimal sufficient adjustment set(s) of variables for multivariable analyses. Analyses were performed on the whole group as well as separately for lobar and deep ICH.ResultsWe analyzed 3,173 patients (1,471 lobar ICH and 1,702 deep ICH) and 3,155 controls. After adjusting for the preselected variables in the minimal sufficient adjustments, heavy alcohol intake was associated with deep ICH risk (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.36–2.09) as well as with the overall risk of ICH (OR, 1.38; 95% CI, 1.17–1.63), whereas no effect was found for lobar ICH (OR, 1.01; 95% CI, 0.77–1.32).ConclusionsIn white people aged 55 years and older, high alcohol intake might exert a causal effect on ICH, with a prominent role in the vascular pathologies underlying deep ICH.

scholarly journals An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xue Li ◽  
Jos van Geffen ◽  
Michiel van Weele ◽  
Xiaomeng Zhang ◽  
Yazhou He ◽  
...  
Keyword(s):  
Vitamin D ◽  
Respiratory Infections ◽  
Causal Effect ◽  
Vitamin D Supplementation ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Uvb Radiation ◽  
Uk Biobank ◽  
Vitamin D Levels ◽  
Weighted Median

AbstractA growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55–1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55–0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42–0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66–0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.

scholarly journals Causal Relationship Between Parathyroid Hormone and the Risk of Osteoarthritis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Guiwu Huang ◽  
Yanlin Zhong ◽  
Wenchang Li ◽  
Weiming Liao ◽  
Peihui Wu
Keyword(s):  
Parathyroid Hormone ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Inverse Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median

BackgroundPrevious studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA.Materials and MethodsWe performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR–Egger method, and “leave-one-out” analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test.ResultsFive single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p &lt; 5 × 10–8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50–0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60–0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors.ConclusionMR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.

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