Evidence For Causal Association Research Articles

Association between glioma and neurodegenerative diseases risk: a two-sample bi-directional Mendelian randomization analysis.

Earlier observational studies have demonstrated a correlation between glioma and the risk of neurodegenerative diseases (NDs), but the causality and direction of their associations remain unclear. The objective of this study was to ascertain the causal link between glioma and NDs using Mendelian randomization (MR) methodology. Genome-wide association study (GWAS) data were used in a two-sample bi-directional MR analysis. From the largest meta-analysis GWAS, encompassing 18,169 controls and 12,488 cases, summary statistics data on gliomas was extracted. Summarized statistics for NDs, including Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) were obtained from the GWAS of European ancestry. Inverse variance weighted (IVW) method was elected as the core MR approach with weighted median (WM) method and MR-Egger method as complementary methods. In addition, sensitivity analyses were performed. A Bonferroni correction was used to correct the results. Genetically predicted glioma had been related to decreased risk of AD. Specifically, for all glioma (IVW: OR = 0.93, 95% CI = 0.90-0.96, p = 4.88 × 10-6) and glioblastoma (GBM) (IVW: OR = 0.93, 95% CI = 0.91-0.95, p = 5.11 × 10-9). We also found that genetically predicted all glioma has a suggestive causative association with MS (IVW: OR = 0.90, 95% CI = 0.81-1.00, p = 0.045). There was no evidence of causal association between glioma and ALS or PD. According to the results of reverse MR analysis, no discernible causal connection of NDs was found on glioma. Sensitivity analyses validated the robustness of the above associations. We report evidence in support of potential causal associations of different glioma subtypes with AD and MS. More studies are required to uncover the underlying mechanisms of these findings.

Type 2 diabetes, glycaemic traits, structural brain capacity and cognitive function: A Mendelian randomization analysis.

To estimate the causal associations of type 2 diabetes and glycaemic traits with cognitive function, and to determine the potential mediating role of various brain imaging-derived phenotypes (IDPs) using Mendelian randomization (MR) analysis. Using publicly available summary data, we performed a series of univariable and multivariable MR analysis to infer causality. Two-step MR analysis was then conducted in turn to evaluate the potential mediating role of each brain IDP. There was no evidence of causal associations between type 2 diabetes and cognitive function outcomes. Each 1-SD unit higher genetically predicted fasting proinsulin was associated with worse cognitive performance, as evidenced by both univariable (beta: -0.022; 95% confidence interval [CI] -0.038, -0.007) and multivariable MR analysis (beta: -0.027; 95% CI -0.048, -0.005). In addition, the univariable MR analysis identified several causal associations between fasting proinsulin and brain IDPs, and between brain IDPs and cognitive performance. The inverse association of genetically predicted fasting proinsulin with cognitive performance did not attenuate after adjusting for each of the brain IDPs in multivariable MR analysis. The present MR study provided credible evidence for the causal association between genetically predicted fasting proinsulin and cognitive function, informing a potential diagnosis and intervention target for patients with cognitive impairment. No significant brain IDP included in this study was identified as lying on the causal pathway from fasting proinsulin to cognitive performance. Future research involving more specific and granular brain IDP or other brain process is warranted to explore the potential biological mechanism underlying the association.

Thyroid function effect on cardiac structure, cardiac function, and disease risk: Evidence of causal associations in European ancestry

BackgroundThyroid hormones play a crucial role in cardiovascular physiology. Subclinical thyroid dysfunction has been associated with adverse cardiovascular outcomes, but evidence is mixed regarding causality. ObjectiveThe purpose of this study was to investigate the potential causal relationships of thyroid-stimulating hormone (TSH), free thyroxine, hypothyroidism, and hyperthyroidism with cardiovascular outcomes, including atrial fibrillation (AF), coronary artery disease, myocardial infarction, heart failure, and ischemic stroke, as well as their effect on cardiac structure and function assessed by cardiac magnetic resonance imaging. MethodsA comprehensive 2-sample Mendelian randomization analysis was performed using summary data from large-scale meta-analyses of European ancestry individuals. ResultsGenetically determined lower TSH levels (odds ratio 0.928; 95% confidence interval 0.884–0.974; P = .003) and genetic risk of hyperthyroidism (odds ratio 1.049; 95% confidence interval 1.016–1.083; P = .003) were associated with increased AF risk. These associations remained significant even after adjusting for cardiovascular risk factors. Colocalization and multivariable Mendelian randomization revealed height as a key mediator between TSH/hyperthyroidism and AF. These findings were further corroborated in the independent FinnGen cohort. However, no clear evidence was found for relationships between thyroid function and other cardiovascular outcomes and cardiac structure and function. ConclusionOur study shows that reduced TSH levels and hyperthyroidism heighten AF risk, with height serving as an important mediator in these associations. The primary focus of thyroid management in cardiovascular health should be on preventing and treating arrhythmias, particularly AF. Our research highlights the importance of routine screening and timely treatment of thyroid dysfunction to optimize the prevention and management of arrhythmias.

Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis.

The causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method. The genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran's Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results. In the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685-1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739-1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826-1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849-1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879-1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680-1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486-1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693-1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis. According to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.

Erythritol as a Potential Causal Contributor to Cardiometabolic Disease: A Mendelian Randomization Study.

People with type 2 diabetes frequently use low-calorie sweeteners to manage glycemia and reduce caloric intake. Use of erythritol, a low-calorie sweetener, has increased recently. Higher circulating concentration associates with major cardiac events and metabolic disease in observational data, prompting some concern. As observational data may be prone to confounding and reverse causality, we undertook bidirectional Mendelian randomization (MR) to investigate potential causal associations between erythritol and coronary artery disease (CAD), body mass index (BMI), waist-hip-ratio (WHR), glycemic and renal traits in cohorts of European ancestry. Analyses were undertaken using instruments comprising genome-wide-significant variants from three cohorts with erythritol measurement. Across instruments, we did not find supportive evidence that increased erythritol increases CAD (b=-0.033±0.02, p=0.14; b=0.46±0.37, p=0.23). MR indicates erythritol may decrease BMI (b=-0.04±0.018, p=0.03; b=-0.04±0.0085, p=1.23x10-5; b=-0.083±0.092, p=0.036) with potential evidence from one instrument of increased BMI adjusted for waist-hip ratio (b=0.046±0.022, p=0.035). No evidence of causal association was found with other traits. In conclusion, we did not find supportive evidence from MR that erythritol increases cardiometabolic disease. These findings await confirmation in well-designed prospective studies.

Abstract 14266: Is the Association Between Coronary Artery Disease and Adverse Brain Health Causal? A Combined Observational and Mendelian Randomisation Study

Introduction: Although coronary artery disease (CAD) is associated with worse brain health in observational studies, whether this is causal remains elusive. Aim: To examine observational associations between CAD and brain health, and use Mendelian randomisation (MR) to test for causal relationships. Methods: 472,120 UK Biobank participants were included. Outcomes were divided into brain morphology (white matter hyperintensity volumes [WMHVs] and hippocampal volumes [HVs]) and cognitive outcomes (reaction times [RTs] and visual memory [VM]). Generalized linear models were employed to explore the association between CAD and these brain health outcomes after adjusting for demographics, cardiometabolic risk factors and medications. To determine whether the observed associations were causal, we fitted MR inverse-variance weighted models, alongside sensitivity analyses for horizontal pleiotropy. Results: Observational analyses showed that CAD participants had 1.8% (95% confidence interval [CI] =[1.5, 2.0]) longer (worse) RTs but this was attenuated to 1% after adjusting for antihypertensives, diabetes or lipid-lowering drugs; 15.9% [7.0, 25.8] greater WMHVs but this was attenuated to the null after controlling for cardiometabolic risk factors; and 1.7% [1.0, 2.5] lower HVs (1% after adjusting for antihypertensives). There was no association between CAD and VM. MR analyses showed that individuals with greater CAD genetic liability made 1.01% [1.00, 1.01] more errors on VM tests but there was no evidence of causal associations with RTs, WMHVs and HVs. Conclusion: Observational analyses showed that CAD was associated with worse brain health, and addressing cardiometabolic risk factors was beneficial. However, MR analyses suggested a causal association only between genetic liability to CAD and worse VM. Future research should explore non-cardiometabolic factors (e.g., glutamate toxicity) to reduce cognitive impairment risk in individuals with CAD.

Developing a prognostic model for stress reduction in patients with prolonged work-related stress.

Mindfulness-based stress reduction (MBSR) is a 9-session group-treatment programme for managing stress. Research suggests variability in the outcomes of MBSR among participants. This prognostic (not causal) study develops a multivariable model that may support clinicians in forecasting expected MBSR outcomes. We used data of 763 patients collected from MBSR programs conducted between October 2015 and March 2022. Candidate prognostic factors at baseline included psychosocial work environment, sociodemographic, and clinical information. Multiple imputation was used to handle missing data (imputations=200). Important prognostic factors were backward selected in ≥5% of the imputed datasets. The final prediction model including the selected prognostic factors was evaluated using linear regression with a four-fold internal cross-validation procedure. Reductions in perceived stress from baseline to end of the MBSR programme were predicted by a lower General Severity Index (β=2.00, p<0.01), higher baseline levels of stress (β=-0.88, p<0.01), and somewhat by having managerial responsibility in the latest job (vs. no; β=-2.53, p=0.07). The remaining prognostic factors were weaker predictors, for example, gender and income. Internal validity of the final model was indicated by consistent results from four randomly folded subsamples. This study developed a prognostic model predicting changes in stress levels in relation to the MBSR programme. A reduction in stress level was particularly predicted by milder psychological symptoms and higher baseline levels of perceived stress. These predictions cannot be taken as evidence of causal associations. Forecasting of the illness course should be cautiously practiced using clinical judgement regarding individual patients.

Multivariate Mendelian randomization provides no evidence for causal associations among both psoriasis and psoriatic arthritis, and skin cancer.

Some retrospective studies reported that psoriasis (PsO) and psoriatic arthritis (PsA) may have been associated with an elevated risk of skin cancer. The causal associations among them remain unclear. To evaluate the causal association of among both PsO and PsA, and skin cancer. We performed large-scale two-sample and Multivariate Mendelian randomization analyses to examine whether there is a causal relationship between PsO and PsA, and skin cancer, encompassing basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and cutaneous melanoma (CM). Genetically predicted PsO, per log-odds ratio increase, showed no significant association with the risk of BCC, cSCC, and CM. The odds ratios (with corresponding 95% confidence intervals) for BCC, cSCC, and CM were 1.00 (0.99,1.01) (PIvw = 0.990), 0.94(0.89, 1.00) (PIvw = 0.065), and 0.99 (0.98, 1.01) (PIvw = 0.239), respectively. PsA showed a significant association with a decreased risk of BCC, with odds ratios (with corresponding 95% confidence intervals) of 1.00 (1.00, 1.00) (PIvw = 0.214) and 1.00 (1.00, 1.00) (PIvw = 0.477), respectively. Univariate analysis of the FinnGen database demonstrated PsA did exhibit a significant association with the decrease risk of BCC, with an odds ratio of 0.94(0.90,0.99) (PIvw = 0.016). However, this association disappeared after other risk factors were adjusted. Our findings suggest no causal association between PsO and PsA and the genetic risk of skin cancer. Further observational studies are required to elucidate the relationship among PsO, PsA, and skin cancer.

A systematic review of the prevalence of pathogenic or likely pathogenic germline variants in individuals with FOXO1 fusion-positive rhabdomyosarcoma.

Several cancer predisposition syndromes (CPS) are reported to predispose to rhabdomyosarcoma, most frequently in children with embryonal rhabdomyosarcoma. There are lingering questions over the role of CPS in individuals with alveolar rhabdomyosarcoma (ARMS), which are frequently driven by FOXO1 fusion oncoproteins. We conducted a systematic review to identify patients with FOXO1 fusion-positive ARMS (FP-ARMS) who underwent germline DNA sequencing. We estimated the prevalence of pathogenic/likely pathogenic (P/LP) variants in cancer predisposing genes (CPGs) and of CPSs. We included 19 publications reporting on 191 patients with FP-ARMS. P/LP variants in CPGs were identified in 26/191 (13.6%) patients, nine (4.9%) of which were associated with a CPS diagnosis. Evidence for causal associations between CPSs and FP-ARMS could not be assessed with available data from this review. Only one patient was affected with a CPS known to predispose to rhabdomyosarcoma, Li-Fraumeni syndrome. Typical CPS associations with rhabdomyosarcoma are rare, but not nonexistent, in patients with FP-ARMS. FOXO1 fusion status, alone, is insufficient for clinicians to rely on to distinguish between patients with/without CPS.

Sleep traits, fat accumulation, and glycemic traits in relation to gastroesophageal reflux disease: A Mendelian randomization study.

Sleep traits, fat accumulation, and glycemic traits are associated with gastroesophageal reflux disease (GERD) in observational studies. However, whether their associations are causal remains unknown. We performed a Mendelian randomization (MR) study to determine these causal relationships. Independent genetic variants associated with insomnia, sleep duration, short sleep duration, body fat percentage, visceral adipose tissue (VAT) mass, type 2 diabetes, fasting glucose, and fasting insulin at the genome-wide significance level were selected as instrumental variables. Summary-level data for GERD were derived from a genome-wide association meta-analysis including 78,707 cases and 288,734 controls of European descent. Inverse variance weighted (IVW) was used for the main analysis, with weighted median and MR-Egger as complements to IVW. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to estimate the stability of the results. The MR study showed the causal relationships of genetically predicted insomnia (odds ratio [OR] = 1.306, 95% confidence interval [CI] 1.261 to 1.352; p = 2.24 × 10-51), short sleep duration (OR = 1.304, 95% CI: 1.147 to 1.483, p = 4.83 × 10-5), body fat percentage (OR = 1.793, 95% CI 1.496 to 2.149; p = 2.68 × 10-10), and visceral adipose tissue (OR = 2.090, 95% CI 1.963 to 2.225; p = 4.42 × 10-117) with the risk of GERD. There was little evidence for causal associations between genetically predicted glycemic traits and GERD. In multivariable analyses, genetically predicted VAT accumulation, insomnia, and decreased sleep duration were associated with an increased risk of GERD. This study suggests the possible roles of insomnia, short sleep, body fat percentage, and visceral adiposity in the development of GERD.

Evidence for Causal Associations Between Prenatal and Postnatal Antibiotic Exposure and Asthma in Children

Evidence for Causal Associations Between Prenatal and Postnatal Antibiotic Exposure and Asthma in Children

Osteoporosis and sarcopenia-related traits: A bi-directional Mendelian randomization study.

BackgroundWith the advancement of world population aging, age-related osteoporosis (OP) and sarcopenia (SP) impose enormous clinical and economic burden on society. Evidence from accumulating studies indicates that they mutually influence one another. However, an observational study may be affected by potential confounders. Meanwhile, a Mendelian randomization (MR) study can overcome these confounders to assess causality.ObjectivesThe aim of this study was to evaluate the causality between OP and SP, informing new strategies for prevention, diagnosis, and treatment of osteosarcopenia.MethodsInstrumental variables (IVs) at the genome‐wide significance level were obtained from published summary statistics, and the inverse variance weighted method and several other MR methods were conducted to evaluate the bi-directional causality between SP and OP. Myopia was analyzed as a negative control outcome to test the validity of IVs.ResultsFemoral neck bone mineral density (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD) had a direct causal effect on appendicular lean mass (ALM) [FA BMD-related analysis: odds ratio (OR) = 1.028, 95% confidence interval (CI) = (1.008,1.049), p = 0.006; FN BMD-related analysis: OR (95% CI) = 1.131 (1.092,1.170), p = 3.18E-12; LS BMD-related analysis: OR (95% CI) = 1.080 (1.062,1.098), p = 2.86E-19]. ALM had a significant causal effect on LS BMD [OR (95% CI) = (1.033,1.147), p = 0.001]. There was no evidence for causal association between BMD and low grip strength.ConclusionsOP and SP might mutually have a significant causal effect on each other. Our results supported the idea that the patient with severe OP was more susceptible to lose ALM and severe ALM loss might reduce LS BMD.

What Characteristics of Epidemiologic Evidence Correlate with Study Usefulness or Influence? Experiences in Three Settings

BACKGROUND AND AIM: Epidemiologic studies play key roles in: 1) environmental chemical risk assessment for setting regulatory standards (US EPA, US states, countries around the globe); and 2) determinations by authoritative bodies (National Academies of Medicine and Science, California Proposition 65 committees, and IARC) that advise on the strength of evidence for present or potential harm to human health and that may be asked to make recommendations. Drawing on experiences in both types of settings, and in an organization that seeks to move environmental health science into the real world, this presentation demonstrates how specific studies become influential. METHODS: Concepts are discussed and will be illustrated through examples (pesticides, cadmium, tetrachlorodibenzo(p)dioxin, radiation; cognitive impairment, lung or breast cancer). RESULTS:For regulatory agencies, epidemiology can play a role in hazard identification, exposure assessment, risk assessment, and risk characterization. In this context, two key features determine the utility of epidemiologic studies: overall quality and rigor; and presence of quantitative exposure measures linked to health outcomes, preferably allowing estimation of an exposure-response relationship. By contrast, panels of the National Academies, IARC, and California Proposition 65 Committees are generally tasked with reviewing a body of research and reaching consensus on the evidence for causal associations between specific exposures and defined health outcomes or on whether exposure prevalence or levels pose a threat to human health. They may also be mandated to provide recommendations. The last setting, Project TENDR (Targeting Environment and NeuroDevelopmental Risks), is more similar in its purpose to authoritative bodies than to risk assessment, but more similar to risk assessment in being directed towards policy or action. CONCLUSIONS:The overarching goals of the program, agency, or panel will determine what study attributes are most valued. The amount, quality and types of evidence will also determine usefulness of epidemiologic studies. Finally, the desirable characteristics may be exposure- or outcome-specific. KEYWORDS: environmental epidemiology, methodology study design, policy and practice

Evidence for causal associations between prenatal and postnatal antibiotic exposure and asthma in children, England.

Higher risks of asthma have been observed in children with prenatal exposure to antibiotics and during early life compared with those who have not. However, the causality of such associations is unclear. To assess whether exposure to antibiotics in early life had a causal effect in increasing the risk of asthma in children diagnosed at 5-8years of life, and the impact in the target population. Data were from electronic health records and questionnaires for children and their mothers in the Born in Bradford birth cohort. Exposure variables were prescriptions of systemic antibiotics to the mother during pregnancy (prenatal) and to the children at 0-24months of life (postnatal). We assessed the association in 12,476 children with several approaches to deal with different sources of bias (triangulation): the interactions with mother's ethnicity, mode of delivery, and between prenatal and postnatal exposures; dose-response; and estimated the population attributable risk. There was an association between prenatal exposure at 7-27days before the child's birth and asthma (adjusted OR=1.40; 1.05, 1.87), but no association with the negative control exposure (before pregnancy) (adjusted OR=0.99 (0.88, 1.12)). For postnatal exposure, the adjusted OR was 2.00 (1.71, 2.34), and for sibling analysis, it was 1.99 (1.00, 3.93). For postnatal exposure, the risk of asthma increased with the number of prescriptions. The observed effect of both exposures was lower among children with mothers of Pakistani ethnicity, but inconclusive (p>.25). The interaction between prenatal and postnatal exposures was also inconclusive (p=.287). The population attributable risk of postnatal exposure for asthma was 4.6% (0.1% for prenatal). We conclude that the associations between both late-pregnancy prenatal exposure to antibiotics and postnatal exposure to antibiotics and an increased risk of asthma are plausible and consistent with a causal effect.

Association between Sleep Traits and Lung Cancer: A Mendelian Randomization Study.

Multidimensional sleep trait, which is related to circadian rhythms closely, affects some cancers predominantly, while the relationship between sleep and lung cancer is rarely illustrated. We aimed to investigate whether sleep is causally associated with risk of lung cancer, through a two-sample Mendelian randomization study. The main analysis used publicly available GWAS summary data from two large consortia (UK Biobank and International Lung Cancer Consortium). Two-sample Mendelian randomization (MR) analysis was used to examine whether chronotype, getting up in the morning, sleep duration, nap during the day, or sleeplessness was causally associated with the risk of lung cancer. Additionally, multivariate MR analysis was also conducted to estimate the direct effects between sleep traits and lung cancer risks independent of smoking status including pack years of smoking or current tobacco smoking. There was no evidence of causal association between chronotype, getting up in the morning, or nap during the day and lung cancer. Sleeplessness was associated with higher risk of lung adenocarcinoma (odds ratio 5.75, 95% confidence intervals 2.12-15.65), while sleep duration played a protective role in lung cancer (0.46, 0.26-0.83). In multivariate MR analysis, sleeplessness and sleep duration remained to have similar results. In conclusion, we found robust evidence for effect of sleeplessness on lung adenocarcinoma risk and inconsistent evidence for a protective effect of sleep duration on lung cancer risk.

Relationship Between Glycemia and Cognitive Function, Structural Brain Outcomes, and Dementia: A Mendelian Randomization Study in the UK Biobank.

We investigated the relationship between glycemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomization (MR). Data were from the UK Biobank (n = ∼500,000). Our exposures were genetic instruments for type 2 diabetes (157 variants) and HbA1c (51 variants) and our outcomes were reaction time (RT), visual memory, hippocampal volume (HV), white matter hyperintensity volume (WMHV), and Alzheimer dementia (AD). We also investigated associations between genetic variants for RT (43 variants) and diabetes and HbA1c We used conventional inverse-variance-weighted (IVW) MR alongside MR sensitivity analyses. Using IVW, genetic liability to type 2 diabetes was not associated with RT (exponentiated β [expβ] = 1.00 [95% CI 1.00; 1.00]), visual memory (expβ = 1.00 [95% CI 0.99; 1.00]), WMHV (expβ = 0.99 [95% CI 0.97; 1.01]), HV (β-coefficient mm3 = -2.30 [95% CI -12.39; 7.78]) or AD (odds ratio [OR] 1.15 [95% CI 0.87; 1.52]). HbA1c was not associated with RT (expβ = 1.00 [95% CI 0.99; 1.02]), visual memory (expβ = 0.99 [95% CI 0.96; 1.02]), WMHV (expβ = 1.03 [95% CI 0.88; 1.22]), HV (β = -21.31 [95% CI -82.96; 40.34]), or risk of AD (OR 1.09 [95% CI 0.42; 2.83]). IVW showed that reaction time was not associated with diabetes risk (OR 0.94 [95% CI 0.54; 1.65]), or with HbA1c (β-coefficient mmol/mol = -0.88 [95% CI = -1.88; 0.13]) after exclusion of a pleiotropic variant. Overall, we observed little evidence of causal association between genetic instruments for type 2 diabetes or peripheral glycemia and some measures of cognition and brain structure in midlife.

Glycemic traits and Alzheimer's disease: a Mendelian randomization study.

Previous observational studies have reported an association between impaired glucose metabolism and Alzheimer’s disease. This study aimed to examine the causal association of glycemic traits with Alzheimer’s disease. We used a two-sample Mendelian randomization approach to evaluate the causal effect of six glycemic traits (type 2 diabetes, fasting glucose, fasting insulin, hemoglobin A1c, homeostasis model assessment- insulin resistance and HOMA-β-cell function) on Alzheimer’s disease. Summary data on the association of single nucleotide polymorphisms with these glycemic traits were obtained from genome-wide association studies of the DIAbetes Genetics Replication And Meta-analysis and Meta-Analyses of Glucose and Insulin-related traits Consortium. Summary data on the association of single nucleotide polymorphisms with Alzheimer’s disease were obtained from the International Genomics of Alzheimer's Project. The Mendelian randomization analysis showed that 1-standard deviation higher fasting glucose and lower HOMA-β-cell function (indicating pancreatic β-cell dysfunction) were causally associated with a substantial increase in risk of Alzheimer’s disease (odds ratio=1.33, 95% confidence interval: 1.04-1.68, p=0.02; odds ratio=1.92, 95% confidence interval: 1.15-3.21, p=0.01). However, no significant association was observed for other glycemic traits. This Mendelian randomization analysis provides evidence of causal associations between glycemic traits, especially high fasting glucose and pancreatic β-cell dysfunction, and high risk of Alzheimer's disease.

Abstract 1201: A mendelian randomization study for the potential causal effect of genetically driven insulin resistance on invasive breast cancer

Abstract Objectives Insulin resistance (IR), traditionally measured by fasting blood levels of glucose (FG) and fasting insulin (FI), has been considered a potential risk factor for breast cancer development. However, findings from previous epidemiologic studies of the relationships between IR and breast cancer were inconsistent, partially due to selection bias, confounding, short time exposure to biomarkers, measurement errors, and reverse causation. We tried to address those challenges by using a Mendelian Randomization (MR) method where FG and FI were analyzed via genetic instrumental variables. Our study aimed to examine the potential causal effect of genetically driven IR on breast cancer development and hoped to understand the underlying mechanisms between IR and breast cancer. Methods We conducted a two-sample MR analysis using the most updated publicly available data from a genome-wide association study (GWAS) of Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC), Breast Cancer Association Consortium (BCAC), and Atlas of GWAS Summary Statistics (ATLAS), focusing on European women. We utilized different datasets for breast cancer outcomes to complement MR analyses with the inverse-variance weighted method. To determine the extent of pleiotropic signal, we applied Cochran's Q test and the MR-Egger regression analysis. Given obesity and diabetes's established role for breast cancer, we excluded those related single-nucleotide polymorphisms (SNPs) from the MR analysis. Results Of 44 SNPs associated with IR, 38 FG SNPs showed slightly positive effects on breast cancer risk across datasets (OncoArray/iCOGS, odds ratio (OR) = 1.002, 95% confidence interval (CI): 0.831- 1.209; ATLAS-General: OR = 1.146, 95% CI: 0.507 - 2.592; ATLAS-GEEA: OR = 1.034, 95% CI: 0.748 - 1.429; ATLAS-GEEAB: OR = 1.029, 95% CI: 0.747 - 1.416). After excluding SNPs associated with diabetes and obesity, the directions of the association between FG and breast cancer in the OncoArray/iCOGS datasets changed but not in the ATLAS-General dataset. Similarly, 6 FI SNPs had a positive association with breast cancer across the datasets. No significant directional pleiotropy was observed. Conclusions Our findings indicate a marginal association between genetically driven IR and breast cancer risk suggesting complex evidence for causal association. Our study may support the potential value of interventions to lower IR, thus reducing breast cancer risk. Citation Format: Sihao Han, Nicholas Mancuso, Zuofeng Zhang, Jeanette Papp, Eric Sobel, Jiemin Yao, Su Yon Jung. A mendelian randomization study for the potential causal effect of genetically driven insulin resistance on invasive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1201.

Cigarette Smoking, Coffee Consumption, Alcohol Intake, and Risk of Crohn's Disease and Ulcerative Colitis: A Mendelian Randomization Study.

Crohn's disease (CD) and ulcerative colitis (UC) are widely associated with smoking in epidemiological studies, whereas there are conflicting results for the association between CD and UC for both coffee and alcohol consumption. Herein, we aimed to investigate whether cigarette smoking and alcohol and coffee consumption are causally associated with either CD or UC. We utilized 540 genome-wide significant single-nucleotide polymorphisms for 3 potentially addictive substances-nicotine, alcohol, and caffeine-to assess the association of smoking, coffee, and alcohol consumption with CD and UC (12,194 CD cases, 12,366 UC cases, and 25,042 controls of European ancestry), using Mendelian randomization analysis. Mendelian randomization estimates were used to evaluate the effect of the exposure factors on CD and UC risk. Sensitivity analysis was employed to test for any directional pleiotropy. We found evidence for a positive causal association between the age of smoking initiation and UC risk and between alcohol consumption and CD risk, which disappeared after sensitivity analysis for both associations (P > 0.05). No evidence for a causal association between cigarettes per day, smoking initiation, smoking cessation, and coffee consumption variables and UC or CD was found. We found no clear evidence that either genetically predicted smoking, coffee consumption, or alcohol consumption are causally associated with the risk for CD or UC, although our findings indicate a potential positive association between the age of smoking and UC and between alcohol consumption and CD.

Emotional distress, stress, and cardiovascular health in adult survivors of childhood cancer.

10547 Background: The contribution of emotional distress and stress to cardiac health in adult survivors of childhood cancer has not been reported, despite evidence of causal associations in the general population. Methods: Comprehensive medical assessments and standardized measures of depression, anxiety, post-traumatic stress disorder, and perceived stress were performed on 3,267 survivors in the St. Jude Lifetime Cohort (median[range] 29.9[18.0-64.5] years of age; 7.7[0-24.8] years at diagnosis; 49% female). Physical outcomes included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia (grades 2-4 per the NCI CTCAE criteria), myocardial infarction (grades 3-4), and metabolic syndrome (yes/no). Multivariable generalized linear models examined associations between these outcomes with any distress/stress, adjusted for demographics, cumulative anthracycline dose and thoracic radiation, physical activity, BMI, smoking, and alcohol intake. Unadjusted longitudinal associations between distress/stress and new onset cardiac conditions were examined among survivors who completed repeat medical assessment(s) (n = 1748; median follow-up = 3.9 years). New onset conditions were defined as a change from grade 0-1 at baseline to ≥ grade 2 at follow-up. Results: Survivor reported distress/stress (29% overall) was more prevalent in those with hypertension (28.2% vs 19.5%, P&lt; 0.001), dyslipidemia (16.4% vs. 11.3%, P&lt; 0.001), diabetes (9.4% vs. 6.9%, P= 0.02), and metabolic syndrome (32.2% vs. 23.2%, P&lt; 0.001), but not among dysrhythmia, cardiomyopathy, and myocardial infarction. In separate multivariable models, distress/stress was associated with hypertension (RR = 1.24, 95% CI 1.07-1.43), dyslipidemia (RR = 1.29, 95% CI 1.03-1.61), and metabolic syndrome (RR = 1.35, 95% CI 1.17-1.54). Baseline distress/stress was associated with new onset hypertension (OR = 1.33, 95% CI 0.94-2.01), dyslipidemia (OR = 1.37, 95% CI 0.94-1.87), and dysrhythmia (OR = 2.78, 95% CI 1.12-6.91). Conclusions: Emotional distress/stress is associated with adverse cardiovascular health and may serve as an intervention target for improving cardiac health outcomes among survivors of childhood cancer.