Genetically Predicted Insomnia in Relation to 14 Cardiovascular Conditions and 17 Cardiometabolic Risk Factors: A Mendelian Randomization Study

Abstract

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.

Human Serum Metabolites as Potential Mediators from Type 2 Diabetes and Obesity to COVID-19 Severity and Susceptibility: Evidence from Mendelian Randomization Study

“…This proportion provided another measure of mediation expressed as the contribution of the metabolite in the causal association between exposure and outcome. We used the multivariate delta method [ 37 , 38 ] to calculate the confidence intervals for the indirect effects and proportions mediated. Metabolites with mediation effects significantly different from 0 were considered as the mediators in the pathway from obesity/T2D to COVID-19.…”

Association between insomnia phenotypes and subclinical myocardial injury: the Multi-Ethnic Study of Atherosclerosis

“…When looking at the association between OSA and cTnT, the regression models were additionally adjusted for insomnia in Model 4. As several traditional CVD risk factors such as hypertension, dyslipidemia, and diabetes are variables that could possibly be on the causal pathway between the association of insomnia phenotypes and CVD, we have not adjusted for these in our models [ 20–22 ]. In addition, analyses were conducted for individual phenotypes, stratified by gender ( Supplementary Tables 1 and 2 ).…”

Potential genetic and epigenetic mechanisms in insomnia: A systematic review

“…In this framework, GWAS SNPs genetic pre‐disposition to insomnia were found to have a significant causal effect on the risk of some mental conditions such as major depression, bipolar disorder type II, schizophrenia, autism spectrum disorder, alcohol, nicotine and opioid use, attention‐deficit/hyperactivity disorder, anxiety and post‐traumatic stress disorder (PTSD), and suicidal behaviours with reverse causality observed for major depression, nicotine use, and PTSD only (Jansen, Dolinoy, et al, 2019, Jansen, Watanabe, et al, 2019; Gao et al, 2019; Song et al, 2020; Pasman et al, 2020; Lewis et al, 2020; Cai et al, 2021; Huang et al, 2021; Carpena et al, 2021; Watanabe et al, 2022; Sun et al, 2022; Baranova et al, 2022; Zhou et al, 2022; Nassan et al, 2022). Similarly, GWAS SNPs genetic pre‐disposition to insomnia were found to have a significant causal one‐way effect on the risk of some medical conditions including: coronavirus disease 2019 (COVID‐19) susceptibility (Peng et al, 2022), cognitive impairment, neurodegenerative conditions (Sun et al, 2020; Zhang et al, 2022), cardiovascular diseases (Jansen, Dolinoy, et al, 2019; Jansen, Watanabe, et al, 2019; Jia et al, 2022; Liu et al, 2021; Zheng et al, 2020), diabetes, cardio‐metabolic risks (Gao et al, 2020; Jansen, Dolinoy, et al, 2019; Jansen, Watanabe, et al, 2019; Liu et al, 2021; Liu et al, 2022), increasing the odds of reporting pain conditions (An et al, 2022; Broberg et al, 2021; Chu et al, 2021; Shu et al, 2022) and for other medical conditions (Bao et al, 2022; He et al, 2022; Huo et al, 2021; Zha et al, 2021).…”