Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study.
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ABSTRACT:
SUBMITTER: Yuan S
PROVIDER: S-EPMC8076146 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: To investigate the causal association of domain-specific sedentary behaviors with cerebrovascular diseases and neurodegenerative diseases, and the potential mediators among these associations. Methods: Genetic instruments were identified for television watching, computer use and driving behavior from a genome-wide association study including 408,815 subjects. Mendelian randomization (MR) analysis was used to estimate the causal effect of sedentary behaviors on the cerebrovascular diseases and neurodegenerative diseases. Multivariable MR analysis was applied to adjust potential confounding factors, and mediation analysis was conducted to explore potential mediators. Results: Genetically predisposition to 1.5 h/day increase in leisure time watching television was associated with increased risk of all-cause stroke [odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15-1.52, p-value for MR-Egger method (P Egger) = 0.11, I 2 = 37%, Cochrane's Q = 212, p-value for Cochran Q test (P Q) < 0.001], and ischemic stroke (OR = 1.28, 95%CI = 1.10-1.49, P Egger = 0.04, I 2 = 35%, Cochrane's Q = 206, P Q = 0.002). Interestingly, television watching may decrease the risk of Parkinson's disease (OR = 0.65, 95%CI = 0.50-0.84, P Egger = 0.47, I 2 = 19%, Cochrane's Q = 157, P Q = 0.04). Television watching was a detrimental factor of cognitive performance (estimate = -0.46, 95%CI = -0.55 - -0.37, P Egger = 0.001, I 2 = 85%, Cochrane's Q = 862, P Q < 0.001). Sensitivity analyses using leave out method and MR-PRESSO method suggested weak evidence of pleiotropy. Conclusion: We provided genetic evidence for the causal association of television watching with increased risk of all-cause stroke and ischemic stroke, decreased risk of Parkinson's disease, and worse cognitive performance. The results should be interpreted with caution considering the pleiotropy.
| S-EPMC8641575 | biostudies-literature
Project description:Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer death worldwide, making its prevention an urgent issue. Meanwhile, the estimated prevalence of insomnia was as high as 30% globally. Research on the causal effect of insomnia on lung cancer incidence is still lacking. In this study, we aimed to assess the causality between the genetic liability to insomnia and lung cancer. We performed a two-sample Mendelian randomization analysis (inverse variance weighted) to determine the causality between the genetic liability to insomnia and lung cancer. Subgroup analysis was conducted, which included lung adenocarcinoma and lung squamous cell carcinoma. In the sensitivity analysis, we conducted heterogeneity test, MR Egger, single SNP analysis, leave-one-out analysis, and MR PRESSO. There were causalities between the genetic susceptibility to insomnia and increased incidence of lung cancer [odds ratio (95% confidence interval), 1.35 (1.14-1.59); P, < 0.001], lung adenocarcinoma [odds ratio (95% confidence interval), 1.35 (1.07-1.70); P, 0.01], and lung squamous cell carcinoma [odds ratio (95% confidence interval), 1.35 (1.06-1.72), P, 0.02]. No violation of Mendelian randomization assumptions was observed in the sensitivity analysis. There was a causal relationship between the genetic susceptibility to insomnia and the lung cancer, which was also observed in lung adenocarcinoma and lung squamous cell carcinoma. The underlying mechanism remains unknown. Effective intervention and management for insomnia were recommended to improve the sleep quality and to prevent lung cancer. Moreover, regular screening for lung cancer may be beneficial for patients with insomnia.
| S-EPMC8672094 | biostudies-literature
Project description:OBJECTIVES:To investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes. DESIGN:Mendelian randomisation study. SETTING:UK Biobank and international genome-wide association study data. PARTICIPANTS:Predominantly participants of European ancestry. EXPOSURE:Educational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation. MAIN OUTCOMES MEASURE:The risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively. RESULTS:Each additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease. CONCLUSIONS:BMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.
| S-EPMC6529852 | biostudies-other
Project description:Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMplusC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes ?5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma ?-linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma ?-linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.
| S-EPMC6950527 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Abnormal serum IGF-1 levels are associated with an increased risk of type 2 diabetes and cardiovascular disease. However, the causal role of IGF-1 levels within the normal range in cardiometabolic disease remains unclear. We employed Mendelian randomisation to explore the associations between genetically predicted serum IGF-1 levels and cardiometabolic diseases. METHODS:Serum IGF-1 levels were predicted using 416 SNPs associated with IGF-1 levels among 358,072 individuals in UK Biobank. Genetic association estimates for the outcomes were obtained from consortia of type 2 diabetes (74,124 cases, 824,006 controls), coronary artery disease (60,801 cases, 123,504 controls), heart failure (47,309 cases, 930,014 controls), atrial fibrillation (65,446 cases, 522,744 controls), and ischaemic stroke (60,341 cases, 454,450 controls). RESULTS:Genetic predisposition to elevated serum IGF-1 levels was associated with higher risk of type 2 diabetes and coronary artery disease. The OR (95% CI) per SD increment in IGF-1 level was 1.14 (1.05, 1.24) for type 2 diabetes and 1.09 (1.02, 1.16) for coronary artery disease. The association between IGF-1 and coronary artery disease was attenuated after adjustment for type 2 diabetes (OR 1.06 [95% CI 1.00, 1.13]), suggesting that the association may be partly mediated via type 2 diabetes. There was limited evidence of associations between IGF-1 levels and heart failure, atrial fibrillation and ischaemic stroke. CONCLUSIONS/INTERPRETATION:This study found evidence that increased IGF-1 levels may be causally associated with higher risk of type 2 diabetes. Graphical abstract.
| S-EPMC7406523 | biostudies-literature
Project description:BackgroundSeveral studies have reported a protective role of circulating α-Klotho on cardiovascular diseases (CVD); however, the causality remains unclear. We aim to elucidate whether genetically predicted circulating α-Klotho levels were causally associated with the risk of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, ischemic stroke (IS), and IS subtypes.MethodsA two-sample Mendelian randomization (MR) study was designed, with 5 single-nucleotide polymorphisms associated with circulating α-Klotho levels utilized as instrumental variables. MR estimates on each CVD outcome derived from the fixed-effects inverse-variance weighted (IVW) approach in different data sources were combined by the fixed-effects meta-analysis approach, complemented by several sensitivity analyses including the simple median, the weighed median, MR-Egger regression, and MR-pleiotropy residual sum and outlier.ResultsIn the meta-analysis combining different data sources, suggestive inverse causal association of circulating α-Klotho concentrations with CAD [Odds ratio (OR), 0.97; 95% confidence interval (CI), 0.94, 1.00; P = 0.044] and significant inverse association of circulating α-Klotho concentrations with AF (OR, 0.96; 95% CI, 0.93, 0.99; P = 0.005) was observed. However, there was no causal association of α-Klotho with HF, any stroke, IS, or IS subtypes neither in different data sources nor in the meta-analysis. Complementary sensitivity analyses showed consistent and robust results in general.ConclusionEvidence was found for a protective effect of circulating α-Klotho on the prevention of AF risk. However, no significant causal association between genetically predicted circulating α-Klotho levels and risk of CAD, HF, stroke, IS, or IS subtypes was found.
| S-EPMC8859151 | biostudies-literature
Project description:Mendelian randomisation studies from Asia suggest detrimental influences of alcohol on cardiovascular risk factors, but such associations are observed mainly in men. The absence of associations of genetic variants (e.g. rs671 in ALDH2) with such risk factors in women - who drank little in these populations - provides evidence that the observations are not due to genetic pleiotropy. Here, we present a Mendelian randomisation study in a South Korean population (3,365 men and 3,787 women) that 1) provides robust evidence that alcohol consumption adversely affects several cardiovascular disease risk factors, including blood pressure, waist to hip ratio, fasting blood glucose and triglyceride levels. Alcohol also increases HDL cholesterol and lowers LDL cholesterol. Our study also 2) replicates sex differences in associations which suggests pleiotropy does not underlie the associations, 3) provides further evidence that association is not due to pleiotropy by showing null effects in male non-drinkers, and 4) illustrates a way to measure population-level association where alcohol intake is stratified by sex. In conclusion, population-level instrumental variable estimation (utilizing interaction of rs671 in ALDH2 and sex as an instrument) strengthens causal inference regarding the largely adverse influence of alcohol intake on cardiovascular health in an Asian population.
| S-EPMC4685310 | biostudies-literature
Project description:BackgroundDespite 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.MethodsWe 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.ResultsGenetically 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.ConclusionOur 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.
| S-EPMC8505411 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Observational studies have shown a bidirectional association between major depressive disorder (MDD) and cardiometabolic diseases. We conducted a two-sample bidirectional Mendelian randomisation (MR) study to assess the causal associations of MDD with type 2 diabetes, coronary artery disease (CAD) and heart failure and vice versa. METHODS:We extracted summary-level data for MDD, type 2 diabetes, CAD and heart failure from corresponding published large genome-wide association studies of individuals mainly of European-descent. In total, 96 SNPs for MDD, 202 SNPs for type 2 diabetes, 44 SNPs for CAD and 12 SNPs for heart failure were proposed as instrumental variables at the genome-wide significance level (p?<?5?×?10-8). The random-effects inverse-variance weighted method was used for the main analyses. RESULTS:Genetic liability to MDD was significantly associated with type 2 diabetes and CAD at the Bonferroni-corrected significance level. The ORs of type 2 diabetes and CAD were respectively 1.26 (95% CI 1.10, 1.43; p?=?6?×?10-4) and 1.16 (95% CI 1.05, 1.29; p?=?0.0047) per one-unit increase in loge odds of MDD. There was a suggestive association between MDD and heart failure (OR 1.11 [95% CI 1.01, 1.21]; p?=?0.033). We found limited evidence supporting causal effects of cardiometabolic diseases on MDD risk in the reverse MR analyses. CONCLUSIONS/INTERPRETATION:The present study strengthened the evidence that MDD is a potential risk factor for type 2 diabetes and CAD. Whether MDD is causally related to heart failure needs further study. DATA AVAILABILITY:All data included in this study were uploaded as supplements and are also publicly available through published GWASs and open GWAS datasets (UK Biobank, 23andMe and Psychiatric Genomics: https://datashare.is.ed.ac.uk/handle/10283/3203; DIAGRAM: http://diagram-consortium.org/downloads.html; CARDIoGRAMplusCD4: www.cardiogramplusc4d.org/; HERMES: http://www.kp4cd.org/datasets/mi). Graphical abstract.
| S-EPMC7286869 | biostudies-literature
Project description:Background This Mendelian randomization study aims to investigate causal associations between genetically predicted insomnia and 14 cardiovascular diseases (CVDs) as well as the potential mediator role of 17 cardiometabolic risk factors. Methods and Results Using genetic association estimates from large genome-wide association studies and UK Biobank, we performed a 2-sample Mendelian randomization analysis to estimate the associations of insomnia with 14 CVD conditions in the primary analysis. Then mediation analysis was conducted to explore the potential mediator role of 17 cardiometabolic risk factors using a network Mendelian randomization design. After correcting for multiple testing, genetically predicted insomnia was consistent significantly positively associated with 9 of 14 CVDs, those odds ratios ranged from 1.13 (95% CI, 1.08-1.18) for atrial fibrillation to 1.24 (95% CI, 1.16-1.32) for heart failure. Moreover, genetically predicted insomnia was consistently associated with higher body mass index, triglycerides, and lower high-density lipoprotein cholesterol, each of which may act as a mediator in the causal pathway from insomnia to several CVD outcomes. Additionally, we found very little evidence to support a causal link between insomnia with abdominal aortic aneurysm, thoracic aortic aneurysm, total cholesterol, low-density lipoprotein cholesterol, glycemic traits, renal function, and heart rate increase during exercise. Finally, we found no evidence of causal associations of genetically predicted body mass index, high-density lipoprotein cholesterol, or triglycerides on insomnia. Conclusions This study provides evidence that insomnia is associated with 9 of 14 CVD outcomes, some of which may be partially mediated by 1 or more of higher body mass index, triglycerides, and lower high-density lipoprotein cholesterol.
| S-EPMC8475657 | biostudies-literature