The causal role of insomnia in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

doi:10.21203/rs.3.rs-3239691/v1

Download PDF

Research Article

The causal role of insomnia in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

https://doi.org/10.21203/rs.3.rs-3239691/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Insomnia is a significant public health issue interconnected with multiple chronic diseases, though the causal association remains elusive. Thus, the objective of this investigation is to undertake a meta-analysis of relevant Mendelian randomization research endeavors to validate the causal connection between insomnia and a spectrum of persistent afflictions.

Methods: The study searched databases for Mendelian randomization(MR) studies exploring the causal relationship between insomnia and chronic diseases, extracted data, and performed quality assessment. A meta-analysis was performed based on all MR studies that met the criteria and on the results of a de novo analysis based on data from the FinnGen consortium.

Results: Genetically predicted insomnia was associated with an increased risk of type 2 diabetes mellitus, 13 circulatory disease, 7 neuropsychological diseases, 3 digestive diseases, 10 pain diseases, asthma, and osteoarthritis as well as cancers of the respiratory system. In contrast, genetically predicted insomnia was not associated with 4 circulatory diseases, 8 neuropsychological diseases, 4 digestive diseases, tuberculosis, and 2 skeletal musculature diseases.

Conclusions: Insomnia has a causal association with numerous chronic diseases. Timely identification and management of insomnia are essential to prevent secondary illnesses, improve quality of life, and optimize healthcare resource utilization.

insomnia

Mendelian randomization

digestive disorders

cardiovascular diseases

chronic diseases.

In recent years, insomnia has emerged as a significant economic burden on public health^[1], and previous observational studies have highlighted a strong association between insomnia and various chronic diseases^[2–4]. However, the causal relationship between insomnia and these diseases remains unclear. Over the past few years, there has been a surge in Mendelian randomization (MR) studies examining insomnia in connection with chronic diseases.

MR is an analytical technique in epidemiology that utilizes genetic variation as instrumental variables to explore causal relationships between exposure factors and outcome events. The advantages of MR lie in the fact that genetic variation is random and therefore less influenced by environmental factors and lifestyle, thus minimizing bias caused by residual confounding ^[5]. Additionally, the use of genetic variation eliminates the possibility of reverse causality in the analysis, as genetic variation does not change due to disease status. The application of this method in studying causal relationships between diseases can aid in the prediction and prevention of related illnesses, and advance the development of precision medicine. Meta-analysis has been widely used to conduct a comprehensive analysis of multiple MR Studies with the same exposure, including smoking^[6], obesity^[7], and body mass index^[8]. In this study, to determine the causal role of insomnia in multiple chronic diseases, this study performed a systematic review and meta-analysis of relevant MR studies that met the inclusion criteria. We not only used the results of published MR studies but also supplemented them with MR results from a de novo analysis based on GWAS data for relevant diseases from the FinnGen consortium^[9].

Literature search and inclusion criteria

This study is conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 reporting guideline ^[10]. The databases of PubMed and Embase were scrutinized from the date of their inception to April 03, 2022, for the terms "Mendelian randomization", "insomnia", and "sleeplessness". This meta-analysis comprised MR analyses that investigated the causal relationship between insomnia and various chronic diseases, including type 2 diabetes, circulatory, neuropsychiatric, digestive, respiratory, skeletal-muscular, cancer, and addictive diseases. In cases where multiple studies on the same outcome and study population were published, the MR analyses from the study with the highest number of cases or the highest number of genetic variants (if the sample size was the same) were incorporated. There were no restrictions on the number of cases.

Data extraction and quality assessment

The data were independently extracted by two authors(CW and JJ), and any discrepancies were resolved through discussion with a third author(XQW). For each MR study, information was collected as follows: first author's surname, year of publication, outcome disease, number of single nucleotide polymorphisms (SNPs), database source, number of cases and non-cases, sample size, race of the participants, and odds ratios and 95% confidence intervals associated with insomnia and various outcomes based on the inverse-variance weighting(IVW) method. Strengthening Mendelian Randomization Study Reporting Guidelines (STROBE-MR)^{[11, 12]} was used for assessing the quality of the literature.

Statistical analysis

The meta-analysis was conducted based on all Mendelian randomization studies that satisfied the criteria and were published, as well as on the publicly available fifth round of data from the FinnGen consortium. For de novo data from the FinnGen consortium, independent single nucleotide polymorphisms (SNPs) were included if R² < 0.001 and P < 5 × 10^− 8 and kb = 10,000. The data of insomnia (ID: ukb-b-3957) were extracted from the OpenGWAS database (https://gwas.mrcieu.ac.uk/). To ensure that the effect estimates and outcomes of each SNP on insomnia corresponded to the same effect-producing allele, all insomnia-associated SNPs were harmonized with data from the FinnGen consortium. Disease-related data were analyzed only for those available in the FinnGen consortium. Due to a lack of data from multiple studies on the same disease, a meta-analysis of results from non-European populations was not possible. Data analysis and processing were performed using the 'meta' package(version 6.2.1) in R software. Finally, the odds ratios and 95% confidence intervals obtained after the analysis with IVW method were recorded and included in the analysis, in which insomnia was used as exposure. The level of inter-study heterogeneity was evaluated through the use of I^2[13], where values < 50%, 50–75%, and > 75% indicate low, moderate, and high heterogeneity, respectively. Results were considered statistically significant if P < 0.05. The meta-analysis was carried out using the common effect model, and sensitivity analyses were performed by using random effects models and excluding individual studies one by one. Sensitivity analyses were performed on European populations only, taking into account the potential differential association of insomnia with disease risk in different populations.

Literature search and study selection

A total of 273 relevant results were retrieved from PubMed and Embase, of which 57 articles reported the relationship between insomnia MR study results and one or more related disease outcomes. Ultimately, the present analysis encompassed a total of 113 studies. The flowchart of the study selection process and the final results are shown in Fig. 1.

Study quality and description

The study quality evaluation results are provided in Supplementary Table 1. All studies included the term "Mendelian randomization" in either the title or abstract, provided a rationale and objective for the study, and disclosed the data sources employed. Furthermore, all studies reported the study sample, selection criteria, number of genetic variants, and statistical methods used for preliminary analysis and exposure units. Estimates of relative risk (odds ratio) were presented clearly in tables or Figures. The study limitations were addressed, and the overall interpretation of results, taking into account the limitations and objectives, was sound.

However, in two of the studies, the software utilized for the Mendelian randomization analysis was not specified. Furthermore, two studies failed to report the results of sensitivity analyses utilizing robust MR methods, such as weighted median and MR-Egger regression. The majority of studies used genetic instruments for insomnia obtained from a genome-wide association study conducted on the UK Biobank, with or without the 23andMe GWAS summary statistics. These studies utilized between 13 to 248 SNPs as instrumental variables. Recent MR studies utilized a strict linkage disequilibrium cut-off (R² < 0.001) to select independent SNPs as instrumental variables for insomnia, whereas some studies selected all conditional independent SNPs identified in the genome-wide association study. The majority of MR studies were based on outcome data from one or few studies, a large-scale genetic consortium, or the UK Biobank. The number of MR studies for each disease was 4 for type 2 diabetes, 40 for circulatory disorders, 32 for neuropsychiatric disorders, 8 for digestive disorders, 14 for pain disorders, 3 for musculoskeletal system diseases, and 12 for respiratory disorders(including cancers). Among the selected studies, eight studies included mixed (trans-ancestry) populations. The details and results of the included MR studies^[14–64] and the relevant data from the FinnGen consortium used in the de novo analysis are presented in Supplementary Table 2.

Diabetes

After conducting a meta-analysis of five Mendelian randomization studies, we have discovered that genetically predicted insomnia is linked to an increased risk of type 2 diabetes, with a combined odds ratio of 1.13 (95% CI:1.11–1.16, P < 0.001) and 30% heterogeneity observed among the studies.

Diseases of the circulatory system

The included circulatory ailments encompassed a spectrum of maladies, namely sepsis, heart failure, atrial fibrillation, ischemic heart disease, myocardial infarction, aortic stenosis, coronary artery disease, peripheral artery disease, hypertension, ischemic stroke, hemorrhagic stroke, transient ischemic attack, intracranial hemorrhage, aortic aneurysm, intracranial aneurysm, venous thrombosis, and pulmonary embolism, resulting in a total of seventeen afflictions. Genetically predetermined insomnia exhibited a positive correlation with increased susceptibility to all thirteen circulatory ailments, except atrial fibrillation, intracranial hemorrhage, heart failure, and hemorrhagic stroke, as depicted in Fig. 2and Supplementary Table 2. The most significant association was found with peripheral artery disease (OR = 1.22, 95% CI:1.18–1.26, P < 0.001), followed by intracranial aneurysm (OR = 1.21, 95% CI:1.04–1.41, P = 0.01) and aortic vavle stenosis (OR = 1.19, 95% CI:1.09–1.29, P < 0.001). Insomnia showed a mild association with the risk of heart failure, myocardial infarction, and ischemic heart disease.

Neuropsychiatric diseases

The included neuropsychiatric ailments encompassed a spectrum of disorders, namely Alzheimer's disease, post-traumatic stress disorder, epilepsy, anxiety, autism, bipolar disorder, attention deficit, depression, schizophrenia, age-related macular degeneration, multiple sclerosis, Parkinson's disease, tobacco addiction, alcohol dependence, and suicide, resulting in a total of fifteen conditions. Genetically predetermined insomnia exhibited a positive correlation with increased susceptibility to seven of these neuropsychiatric disorders, as depicted in Fig. 2and Supplementary Table 2. The most significant association was found with post-traumatic stress disorder, followed by autism (OR = 1.71, 95% CI: 1.20–2.44, P = 0.003) and bipolar disorder (OR = 1.43, 95% CI: 1.22–1.68, P < 0.001). Insomnia showed a mild association with the risk of developing tobacco addiction, with an OR range of 1.05 (95% CI: 1.03–1.07).

Digestive system diseases

The digestive disorders that were analyzed encompassed irritable bowel syndrome(IBS), nonalcoholic liver disease, gastroesophageal reflux disease(GORD), peptic ulcer disease(PUD), inflammatory bowel disease(IBD), ulcerative colitis, and Crohn's disease, yielding a total of seven disorders. The findings of this study suggest that genetically predicted insomnia is linked to an increased risk of three of these digestive disorders (Fig. 2, Supplementary Table 2). The strongest association was observed with IBS (OR = 2.60, 95% CI: 1.86–3.64, P < 0.001), followed by GORD (OR = 1.46, 95% CI: 1.42–1.51, P < 0.001) and PUD (OR = 1.19, 95% CI: 1.14–1.24, P < 0.001). Moderate heterogeneity was detected only in the analysis of GORD.

Respiratory system diseases

Insomnia predicted by genetics was found to be associated with an elevated risk of lung cancer, lung adenocarcinoma, and lung squamous carcinoma, but not tuberculosis. Among these diseases, the strongest association was observed with lung adenocarcinoma (OR = 1.24, 95% CI:1.12–1.37, P < 0.001), followed by lung squamous carcinoma (OR = 1.21, 95% CI:1.08–1.35, P < 0.001) and lung cancer (OR = 1.21, 95% CI:1.13–1.30, P < 0.001). Notably, there was moderate heterogeneity between studies in the analysis of asthma, lung cancer, lung adenocarcinoma, and lung squamous carcinoma.

Pain diseases

The pain conditions considered in the study comprised of headache, migraine, back pain, abdominal pain, hip pain, multisite pain, extremity pain, eye pain, chest pain, and low back pain. Genetically predicted insomnia was found to be associated with an increased risk of all ten included pain conditions. Notably, the strongest association was observed for hip pain (OR = 1.96, 95% CI: 1.56–2.14, P < 0.001), followed by multisite pain (OR = 1.77, 95% CI: 1.63–1.94, P < 0.001) and eye pain (OR = 1.71, 95% CI: 1.19–2.45, P = 0.004). However, a high degree of heterogeneity was noted between the hip pain and multisite pain studies.

Musculoskeletal system diseases

The musculoskeletal system disorders that were included in this study comprised abnormalities in heel bone density, osteoarthritis(OA), and rheumatoid arthritis. The findings revealed that genetically predicted insomnia was linked with a higher risk of developing OA (OR = 1.22, 95% CI:1.15–1.30, P < 0.001).

Sensitivity analyses

The current investigation included an analysis of multi-ethnic genetic data for eight disorders, and excluding these data showed that the association between insomnia and bipolar disorder differed from previous findings, as insomnia was not found to be associated with an increased risk of bipolar disorder in European populations (OR = 1.21, 95% CI: 0.98–1.50, P = 0.08). Excluding studies based on multi-ethnic populations had only a minor impact on the outcome of the other seven disorders.

To conduct a systematic evaluation, effect values were combined using different models for sensitivity analysis. In contrast to the fixed-effects model, the random-effects model indicated that insomnia significantly increased the prevalence of heart failure (OR = 1.13, 95% CI: 1.03–1.25, P = 0.009) and was associated with intracranial aneurysm (OR = 1.60, 95% CI: 0.61–4.18, P = 0.33), posttraumatic stress disorder (OR = 1.92, 95% CI: 0.99–3.73, P = 0.05), and tobacco addiction (OR = 1.06, 95% CI: 0.92–1.21, P = 0.43). PUD (OR = 0.96, 95% CI: 0.26–3.59, P = 0.96), and lung adenocarcinoma (OR = 1.73, 95% CI: 0.86–3.48, P = 0.12) were not associated with the risk of development. The results for the other 50 disorders did not change significantly after the model was changed.

In a sensitivity analysis conducted by excluding literature on a case-by-case basis, it was observed that after eliminating Yang's study from the meta-analysis of studies concerning atrial fibrillation, there was no heterogeneity among studies (I² = 0%). The combined effect size results indicated that insomnia could enhance the risk of developing atrial fibrillation (OR = 1.11, 95% CI: 1.08–1.15, P < 0.01), which had a greater impact on the overall effect size and might be the primary source of heterogeneity in the meta-analysis. The results for other diseases remained relatively unchanged when the literature was excluded on a case-by-case basis.

The present meta-analysis incorporates MR studies that examine the genetic prediction of insomnia in association with 57 chronic diseases. The data reveals compelling evidence supporting a causal link between insomnia and heightened risk of 13 circulatory ailments, 7 neuropsychiatric afflictions, type 2 diabetes, lung cancer (including squamous lung cancer and lung adenocarcinoma), 3 digestive diseases, 10 pain conditions, asthma, and OA. Conversely, MR evidence suggests that 3 circulatory disorders (comprising atrial fibrillation, heart attack, and hemorrhagic stroke), 8 neuropsychiatric disorders (including Alzheimer's disease, traumatic stress disorder, epilepsy, attention deficit, schizophrenia, age-related macular degeneration, multiple sclerosis, Parkinson's, and alcohol dependence), 4 digestive disorders (such as nonalcoholic liver disease, IBD, ulcerative colitis, Crohn's disease), tuberculosis, abnormal heel bone density, and rheumatoid arthritis are improbable to be causally related to insomnia.

Previous research suggests that insomnia may have a significant impact on the likelihood of developing type 2 diabetes, as it activates sympathetic nerves, increasing insulin resistance^[65]. Furthermore, insomnia is linked to chronic systemic inflammation, which could contribute to the onset of insulin resistance, ultimately leading to the development of type 2 diabetes^{[66, 67]}. Increased inflammatory markers in individuals suffering from sleep deprivation also play a role in atherosclerosis^{[68, 69]}. Mechanisms that may explain the relationship between short sleep duration and the elevated risk of peripheral arterial disease include activation of the autonomic nervous system, oxidative stress, endothelial dysfunction, impaired metabolic regulation, as well as coagulation system activity^[70]. The development of intracranial aneurysms may be associated with alterations in cerebrovascular health, as a result of insomnia-induced increases in circulating catecholamine levels^[71], sympathetic activity^[71], inflammation^[73–75], and endocrine or metabolic dysregulation^{[76, 77]}. Insomnia is related to hypertension, brought about by increased sympathetic nervous system activity, heart rate, and abnormal hormone secretion^[78], all of which could further contribute to the onset of intracranial hemorrhage. Moreover, insomnia may exacerbate atherosclerosis by abnormal regulation of the hypothalamic-pituitary-adrenal axis^[79] and the renin-angiotensin system^[80], irregular regulation of the autonomic nervous system, increased sympathetic nervous system activity^[81], systemic inflammation, and abnormal lipid metabolites^[82], which may result in plaque rupture and thrombosis, ultimately affecting the risk of coronary heart disease positively. Lastly, insomnia is linked to impaired glucose metabolism^[83] and melatonin secretion^[84], which could also contribute to the onset of coronary heart disease.

Research indicates that insomnia can impact the immune system through multiple pathways, such as pro-inflammatory cytokines, lymphocyte subsets, and telomere length^[85]. This may be a significant factor in the increased risk of bloodstream infections^[86] and immune responses that lead to sepsis associated with insomnia. Insomnia or sleep deprivation has been shown to decrease the number and function of natural killer cells and T cells, thus increasing vulnerability to allergens^{[87, 88]}. Insomnia can also modulate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, causing upregulation of pro-inflammatory responses^{[89, 90]}, β-adrenergic signaling activation, and increases in systemic inflammatory markers, such as NF-κB and pro-inflammatory cytokine production. Among these diseases, allergic asthma is particularly associated with changes in levels of IL-6^[91], NF-κB^{[92, 93]}, and high-sensitivity C-reactive protein (CRP)^[94]. Additionally, insomnia can suppress melatonin, an endocrine hormone with circadian rhythm regulation, immunomodulatory, antioxidant, and cytoprotective effects. This suppression of melatonin also contributes to increased immune disorders and activation of inflammatory pathways^[95].

Disturbances in melatonin secretion are commonly observed in patients with chronic primary insomnia. Furthermore, sleep quality impairment is associated with reduced levels of Klotho, a senescence-inhibitory protein that restrains lung cancer cell proliferation and promotes apoptosis^[96–98]. Certain intermediate phenotypes may be implicated in the connection between insomnia and lung cancer. Indeed, a bidirectional causal relationship exists between insomnia and smoking^[99], with smoking initiation and daily cigarette consumption positively correlated with insomnia. Insomnia is thought to promote heavy smoking while discouraging cessation, given the carcinogenic nature of smoking. Dependence on smoking may thus be an important mediator of the link between insomnia and lung cancer^[100]. Multiple modern studies suggest that dysregulation of biological clock genes^[101], immunosuppression due to sleep deprivation[Bollinger 2010], and changes in melatonin secretion^[102–104] (i.e., timing, amount, and duration) as a result of circadian rhythm disruptions may all contribute to tumorigenesis and development. Melatonin has several antitumor effects, such as regulating the cell cycle and apoptosis, stimulating cell differentiation, antioxidant effects, and protection against dysbiosis, which often occurs in lung cancer patients and may be a potential underlying factor^[105–107].

The brain-gut axis can influence intestinal dynamics, fluid secretion, the permeability of the intestinal epithelium, and the composition of the gut microbiota^[108]. Disturbances in sleep patterns such as insomnia and short sleep duration can contribute to the pathogenesis of IBS through immune system dysfunction^[109], brain-gut axis, and disruption of circadian rhythms^[110]. Plasma levels of inflammatory cytokines such as CRP and IL-6 are notably higher in individuals with insomnia and short sleep durations, and medical research indicates that aberrant sleep patterns have negative effects on gastrointestinal function, increase the likelihood of peptic ulcers, and may be a crucial factor in the development of chronic inflammatory conditions such as PUD^[111]. Sleep deprivation hinders the repair of the gastric mucosa, decreases blood flow to the gastric mucosa, inhibits cell proliferation, and weakens the ionic barrier of the gastric mucosa, potentially resulting in gastric mucosal erosion^[112]. Studies show that deep sleep promotes gastric mucosal outflow and blood flow, as well as melatonin secretion while inhibiting gastrin secretion, which helps to prevent the onset and recurrence of PUD. Melatonin is believed to prevent the recurrence of PUD by promoting cell proliferation, scavenging oxidative free radicals, and enhancing the microcirculation of the gastric mucosa^[113].

Psychiatric disorders, such as anxiety and depressive symptoms, often coincide with IBS, GORD, and PUD, and are associated with a range of biological and psychosocial mechanisms that mainly disrupt the gut-brain axis^[114]. Additionally, sleep behavior plays a critical role in various brain functions, including nerve cell growth, synaptogenesis, and memory function^{[115, 116]}. Freeman et al. conducted a large randomized controlled trial of insomnia-related mental health issues and showed that insomnia is a significant causal risk factor for mental health problems, and remediating sleep disturbance can aid mental health problems such as depression, anxiety, autism, and post-traumatic stress disorder^[117]. Failure to do so may lead to the development of suicidal behavior^[118].

The precise mechanism by which insomnia contributes to OA remains uncertain. However, it is postulated that sleep fragmentation and deprivation may modify the gut microbiota^[119], potentially increasing the likelihood of OA development^{[120, 121]}. Moreover, insomnia may elicit the secretion of pro-inflammatory cytokines, such as IL-6, IL-1β, IL-17, and TNF-α^{[67, 85]}. Sleep disorders also have close associations with melatonin production, which may establish a link between circadian rhythms and OA^{[122, 123]}. Melatonin, in turn, may contribute to OA by regulating the release of chondrogenic degenerative enzymes, pro-inflammatory cytokines, and inflammatory mediators^[124]. Additionally, the link between sleep deprivation, obesity, and OA may be mediated by certain metabolic disorders, such as elevated leptin levels in obese individuals leading to cartilage degeneration^[125].

There is notable consistency in the genetically predicted associations between insomnia and various types of pain, indicating a shared causal pathway between the two conditions. Nitric oxide (NO) is believed to be a critical element in the regulation of sleep-wake balance, with a consequential role in both pain modulation and sleep. Elevated NO levels have been observed in sleep-deprived rats, with NO levels in the basal forebrain being elevated before the elevation of iNOS and NO levels in the frontal cortex. Moreover, raised NO levels promote nociceptive hypersensitivity, as demonstrated by the reduction of mechanical hypersensitivity with the use of neuronal-type nitric oxide synthase (nNOS) inhibitors. In a rat model, sleep deprivation was seen to exacerbate chronic pain, causing severe pain.^[126–129] In addition, another study showed increased basal cortisol levels and hyperresponsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stressors in patients with insomnia, which correlated with the relationship between insomnia and mechanical hypersensitivity^[130]. Prostaglandins (PG), a classic marker of inflammation that mediates inflammatory pain, were found to be significantly elevated in the cerebrospinal fluid of a mouse experiment^[131]. The findings suggest that patients with insomnia experience over-activation of pain inhibitory pathways, leading to pain perception that is independent of pharmacological treatment^[132]. This may be related to the significance of sleep in regulating neurodevelopment and maintenance. Insomnia is also linked to changes in the caudate nucleus neurons that are involved in pain inhibition^{[133, 134]}. Thus, treating insomnia may be critical to mitigating pain.

Upon analysis of genetically predicted insomnia and various disease outcomes, including but not limited to GORD, depression, heart failure, smoking addiction, atrial fibrillation, intracranial hemorrhage, and coronary artery disease, heterogeneity was observed in the estimates obtained from individual studies. This heterogeneity appears to have been caused by varying levels of association across studies, which may be attributed to the use of different genetic instruments or to study populations with different characteristics or ethnicities.

This study is the first systematic review and meta-analysis based on insomnia-related MR studies, which aim to eliminate the potential effects of weak instrumental variables and verify results through multiple sensitivity analyses. While some causal relationships between diseases may be attributed to common risk factors, many MR analyses exclude SNPs that may be influenced by such factors and still support previously found causal relationships. However, this study has limitations, including a lack of sufficient MR studies related to some diseases and the fact that the included results are based on European ancestry and may not apply to other populations. In addition, the definition of insomnia in the GWAS data used in the study, which mainly included difficulty falling asleep and easy awakening, was a subjective classification of sleep characteristics by questionnaire; a more detailed and objective subtype classification would help to explore causal relationships and underlying mechanisms. The time-consuming nature of objective sleep EEG feature extraction and classification also limits the understanding of the causal relationship between insomnia subtypes and chronic diseases based on sleep staging. Finally, this study only examined one-way studies with insomnia as exposure and chronic diseases as outcomes and further meta-analyses are needed to explore reverse MR findings.

The entirety of evidence from both previously published and new Mendelian randomization analyses provides substantial support for the causal association between insomnia and various chronic diseases. As such, a comprehensive strategy is required, encompassing a personalized evaluation and an all-encompassing treatment plan for each patient's distinct circumstances. The timely identification and management of insomnia are crucial to prevent secondary illnesses, enhance the quality of life, and optimize the utilization of healthcare resources.

Author contribution

(i) substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of the data for the work: Chi Wang†, Jing Jiang;

(ii) drafting of the work or revising it critically for important intellectual content: Kai Liu, Xiya Yuan;

(iii) final approval of the version to be published: Wenzhong Wu*;

(iv) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Chengyong Liu, Xiaoqiu Wang, Qingyun Wan.

Funding

This work was supported by the National Natural Science Foundation of China (grant number: 82274631) and the Jiangsu Provincial Department of Science and Technology (grant number: BE2021751).

Competing interests

The authors declare that they have no competing interests.

Ethics approval statement

All the genes used in the research data are from the public database in the large-scale genome-wide association study (GWAS), so the study does not require ethical

approval.

Acknowledgments

We gratefully acknowledge the authors and participants of all GWAS from which we used summary statistics data.

Availability of Data and Materials

The genetic data used for de novo analysis are based on publicly available summary statistics data provided by the FinnGen consortium. Other data analyzed in this study are based on published articles, in references 14 to 64. The details of the data are presented in Supplementary Table 2. More detailed data sets are available from the corresponding author on reasonable request.

Glick DR, Abariga SA, Thomas I, et al. Economic Impact of Insufficient and Disturbed Sleep in the Workplace [published online ahead of print, 2023 Mar 18]. Pharmacoeconomics. 2023;10.1007/s40273-023-01249-8. doi:10.1007/s40273-023-01249-8
Latocha KM, Løppenthin K, Jennum P, Christensen R, Østergaard M, Esbensen BA. Experiences of group-based cognitive behavioural therapy for insomnia among patients with rheumatoid arthritis: a qualitative study. BMJ Open. 2023;13(1):e066221. Published 2023 Jan 3. doi:10.1136/bmjopen-2022-066221
Belachew EA, Sendekie AK, Ayele EM, Netere AK. Prevalence and determinants of insomnia among patients living with asthma in Northwest Ethiopian University specialised hospitals: Multicentre cross-sectional study. BMJ Open. 2022;12(11):e066215. Published 2022 Nov 18. doi:10.1136/bmjopen-2022-066215
Lyall LM, Sangha N, Zhu X, et al. Subjective and objective sleep and circadian parameters as predictors of depression-related outcomes: A machine learning approach in UK Biobank [published online ahead of print, 2023 May 6]. J Affect Disord. 2023;S0165-0327(23)00624-9. doi:10.1016/j.jad.2023.04.138
Haycock PC, Burgess S, Wade KH, Bowden J, Relton C, Davey Smith G. Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies. Am J Clin Nutr. 2016;103(4):965-978. doi:10.3945/ajcn.115.118216
Larsson SC, Burgess S. Appraising the causal role of smoking in multiple diseases: A systematic review and meta-analysis of Mendelian randomization studies. EBioMedicine. 2022;82:104154. doi:10.1016/j.ebiom.2022.104154
Riaz H, Khan MS, Siddiqi TJ, et al. Association Between Obesity and Cardiovascular Outcomes: A Systematic Review and Meta-analysis of Mendelian Randomization Studies. JAMA Netw Open. 2018;1(7):e183788. Published 2018 Nov 2. doi:10.1001/jamanetworkopen.2018.3788
Larsson SC, Burgess S. Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies. BMC Med. 2021;19(1):320. Published 2021 Dec 15. doi:10.1186/s12916-021-02188-x
Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population [published correction appears in Nature. 2023 Feb 24;:]. Nature. 2023;613(7944):508-518. doi:10.1038/s41586-022-05473-8
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Published 2021 Mar 29. doi:10.1136/bmj.n71
Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326(16):1614-1621. doi:10.1001/jama.2021.18236
Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 2020;4:186. Published 2020 Apr 28. doi:10.12688/wellcomeopenres.15555.2
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558. doi:10.1002/sim.1186
Xiuyun W, Jiating L, Minjun X, Weidong L, Qian W, Lizhen L. Network Mendelian randomization study: exploring the causal pathway from insomnia to type 2 diabetes. BMJ Open Diabetes Res Care. 2022;10(1):e002510. doi:10.1136/bmjdrc-2021-002510
Gao X, Yang XC, Meng LX, Sun HL, Wang T. Causal relationship between sleep and coronary artery disease: a Mendelian randomization study.Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(4):611-614. doi:10.3760/cma.j.cn112338-20190624-00462
Gao X, Sun H, Zhang Y, Liu L, Wang J, Wang T. Investigating Causal Relations Between Sleep-Related Traits and Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study. Front Genet. 2020;11:607865. Published 2020 Dec 15. doi:10.3389/fgene.2020.607865
Jia Y, Guo D, Sun L, et al. Diet, Lifestyle Behaviours and Other Risk Factors Associated With Type 2 Diabetes Beyond Body Mass Index: A Mendelian Randomization Study. Can J Diabetes. 2022;46(8):822-828. doi:10.1016/j.jcjd.2022.06.001
Jia Y, Guo D, Sun L, et al. Self-reported daytime napping, daytime sleepiness, and other sleep phenotypes in the development of cardiometabolic diseases: a Mendelian randomization study. Eur J Prev Cardiol. 2022;29(15):1982-1991. doi:10.1093/eurjpc/zwac123
Larsson SC, Markus HS. Genetic Liability to Insomnia and Cardiovascular Disease Risk. Circulation. 2019;140(9):796-798. doi:10.1161/CIRCULATIONAHA.119.041830
Liu X, Li C, Sun X, et al. Genetically Predicted Insomnia in Relation to 14 Cardiovascular Conditions and 17 Cardiometabolic Risk Factors: A Mendelian Randomization Study. J Am Heart Assoc. 2021;10(15):e020187. doi:10.1161/JAHA.120.020187
Liao LZ, Li WD, Liu Y, Li JP, Zhuang XD, Liao XX. Causal assessment of sleep on coronary heart disease. Sleep Med. 2020;67:232-236. doi:10.1016/j.sleep.2019.08.014
Cai H, Liang J, Liu Z, et al. Causal Effects of Sleep Traits on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study. Nat Sci Sleep. 2020;12:783-790. Published 2020 Oct 21. doi:10.2147/NSS.S265946
van Oort S, Beulens JWJ, van Ballegooijen AJ, Grobbee DE, Larsson SC. Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Hypertension: A Mendelian Randomization Study. Hypertension. 2020;76(6):1971-1979. doi:10.1161/HYPERTENSIONAHA.120.15761
Larsson SC, Markus HS. Genetic Liability to Insomnia and Cardiovascular Disease Risk. Circulation. 2019;140(9):796-798. doi:10.1161/CIRCULATIONAHA.119.041830
Hoek AG, van Oort S, Elders PJM, Beulens JWJ. Causal Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Peripheral Artery Disease: A Mendelian Randomization Approach. J Am Heart Assoc. 2022;11(16):e025644. doi:10.1161/JAHA.122.025644
Yang Y, Fan J, Shi X, et al. Causal associations between sleep traits and four cardiac diseases: a Mendelian randomization study. ESC Heart Fail. 2022;9(5):3160-3166. doi:10.1002/ehf2.14016
Zhang Z, Wang M, Gill D, Zhu W, Liu X. Genetically Predicted Sleep Traits and Functional Outcome After Ischemic Stroke: A Mendelian Randomization Study. Neurology. 2023;100(11):e1159-e1165. doi:10.1212/WNL.0000000000206745
Peng P, Chen Z, Zhang X, et al. Investigating Causal Relationships Between Psychiatric Traits and Intracranial Aneurysms: A Bi-directional Two-Sample Mendelian Randomization Study. Front Genet. 2021;12:741429. Published 2021 Oct 19. doi:10.3389/fgene.2021.741429
Karhunen V, Bakker MK, Ruigrok YM, Gill D, Larsson SC. Modifiable Risk Factors for Intracranial Aneurysm and Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study. J Am Heart Assoc. 2021;10(22):e022277. doi:10.1161/JAHA.121.022277
Zhou F, Guo Y, Wang Z, Liu S, Xu H. Assessing the causal associations of insomnia with depressive symptoms and subjective well-being: a bidirectional Mendelian randomization study. Sleep Med. 2021;87:85-91. doi:10.1016/j.sleep.2021.08.025
Cai L, Bao Y, Fu X, et al. Causal links between major depressive disorder and insomnia: A Mendelian randomisation study. Gene. 2021;768:145271. doi:10.1016/j.gene.2020.145271
Pasman JA, Smit DJA, Kingma L, Vink JM, Treur JL, Verweij KJH. Causal relationships between substance use and insomnia [published correction appears in Drug Alcohol Depend. 2020 Nov 1;216:108313]. Drug Alcohol Depend. 2020;214:108151. doi:10.1016/j.drugalcdep.2020.108151
Nassan M, Daghlas I, Winkelman JW, Dashti HS; International Suicide Genetics Consortium, Saxena R. Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study. Neuropsychopharmacology. 2022;47(9):1672-1679. doi:10.1038/s41386-022-01319-z
Zhou F, Li S, Xu H. Insomnia, sleep duration, and risk of anxiety: A two-sample Mendelian randomization study. J Psychiatr Res. 2022;155:219-225. doi:10.1016/j.jpsychires.2022.08.012
Lim KX, Oginni OA, Rimfeld K, Pingault JB, Rijsdijk F. Investigating the causal risk factors for self-harm by integrating Mendelian randomisation within twin modelling [published correction appears in Behav Genet. 2022 Oct 11;:]. Behav Genet. 2022;52(6):324-337. doi:10.1007/s10519-022-10114-x
Anderson EL, Richmond RC, Jones SE, et al. Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis. Int J Epidemiol. 2021;50(3):817-828. doi:10.1093/ije/dyaa183
Yuan S, Tomson T, Larsson SC. Modifiable risk factors for epilepsy: A two-sample Mendelian randomization study. Brain Behav. 2021;11(5):e02098. doi:10.1002/brb3.2098
Lind MJ, Brick LA, Gehrman PR, et al. Molecular genetic overlap between posttraumatic stress disorder and sleep phenotypes. Sleep. 2020;43(4):zsz257. doi:10.1093/sleep/zsz257
Baranova A, Cao H, Zhang F. Shared genetic liability and causal effects between major depressive disorder and insomnia. Hum Mol Genet. 2022;31(8):1336-1345. doi:10.1093/hmg/ddab328
Chen D, Wang X, Huang T, Jia J. Sleep and Late-Onset Alzheimer's Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects. Front Genet. 2022;13:794202. Published 2022 May 17. doi:10.3389/fgene.2022.794202
Huang J, Zuber V, Matthews PM, Elliott P, Tzoulaki J, Dehghan A. Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study. Neurology. 2020;95(14):e1963-e1970. doi:10.1212/WNL.0000000000010463
Grover S, Sharma M; International Age-related Macular Degeneration Genomics Consortium (IAMDGC). Sleep, Pain, and Neurodegeneration: A Mendelian Randomization Study. Front Neurol. 2022;13:765321. Published 2022 May 2. doi:10.3389/fneur.2022.765321
Gao X, Meng LX, Ma KL, et al. The bidirectional causal relationships of insomnia with five major psychiatric disorders: A Mendelian randomization study. Eur Psychiatry. 2019;60:79-85. doi:10.1016/j.eurpsy.2019.05.004
Huang P, Zou Y, Zhang X, et al. The Causal Effects of Insomnia on Bipolar Disorder, Depression, and Schizophrenia: A Two-Sample Mendelian Randomization Study. Front Genet. 2021;12:763259. Published 2021 Oct 11. doi:10.3389/fgene.2021.763259
Huang P, Zou Y, Zhang X, et al. The Causal Effects of Insomnia on Bipolar Disorder, Depression, and Schizophrenia: A Two-Sample Mendelian Randomization Study. Front Genet. 2021;12:763259. Published 2021 Oct 11. doi:10.3389/fgene.2021.763259
Chen M, Peng WY, Tang TC, Zheng H. Differential Sleep Traits Have No Causal Effect on Inflammatory Bowel Diseases: A Mendelian Randomization Study. Front Pharmacol. 2021;12:763649. Published 2021 Nov 30. doi:10.3389/fphar.2021.763649
Zha LF, Dong JT, Wang JL, et al. Effects of Insomnia on Peptic Ulcer Disease Using Mendelian Randomization. Oxid Med Cell Longev. 2021;2021:2216314. Published 2021 Sep 25. doi:10.1155/2021/2216314
Sun Y, Cao X, Cao D, et al. Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease. Front Nutr. 2022;9:1009122. Published 2022 Nov 1. doi:10.3389/fnut.2022.1009122
Fan H, Liu Z, Zhang X, et al. Investigating the Association Between Seven Sleep Traits and Nonalcoholic Fatty Liver Disease: Observational and Mendelian Randomization Study. Front Genet. 2022;13:792558. Published 2022 May 17. doi:10.3389/fgene.2022.792558
Wang J, Tang H, Duan Y, Yang S, An J. Association between Sleep Traits and Lung Cancer: A Mendelian Randomization Study. J Immunol Res. 2021;2021:1893882. Published 2021 Jun 21. doi:10.1155/2021/1893882
Zhang S, Zhang W, Feng Y, et al. Causal relationship between insomnia and tuberculosis: A bi-directional Mendelian randomization analysis. Medicine (Baltimore). 2022;101(37):e30509. doi:10.1097/MD.0000000000030509
Kim DJ, Ha TW, Jung HU, et al. Characterisation of insomnia as an environmental risk factor for asthma via Mendelian randomization and gene environment interaction. Sci Rep. 2021;11(1):21813. Published 2021 Nov 8. doi:10.1038/s41598-021-01291-6
Li R, Chen Y, Zhao A, et al. Exploring genetic association of insomnia with allergic disease and asthma: a bidirectional Mendelian randomization study. Respir Res. 2022;23(1):84. Published 2022 Apr 7. doi:10.1186/s12931-022-02009-6
Shen J, Zhou H, Liu J, et al. Genetic Liability to Insomnia and Lung Cancer Risk: A Mendelian Randomization Analysis. Front Genet. 2021;12:756908. Published 2021 Dec 1. doi:10.3389/fgene.2021.756908
Huo Z, Ge F, Li C, et al. Genetically predicted insomnia and lung cancer risk: a Mendelian randomization study. Sleep Med. 2021;87:183-190. doi:10.1016/j.sleep.2021.06.044
Chu S, Wu Z, Wu Z, Wu J, Qian Y. Association Between Insomnia and Migraine Risk: A Case-Control and Bidirectional Mendelian Randomization Study. Pharmgenomics Pers Med. 2021;14:971-976. Published 2021 Aug 13. doi:10.2147/PGPM.S305780
Shu P, Ji L, Ping Z, Sun Z, Liu W. Association of insomnia and daytime sleepiness with low back pain: A bidirectional mendelian randomization analysis. Front Genet. 2022;13:938334. Published 2022 Oct 4. doi:10.3389/fgene.2022.938334
Luo G, Yao Y, Tao J, Wang T, Yan M. Causal association of sleep disturbances and low back pain: A bidirectional two-sample Mendelian randomization study. Front Neurosci. 2022;16:1074605. Published 2022 Dec 2. doi:10.3389/fnins.2022.1074605
Daghlas I, Vgontzas A, Guo Y, Chasman DI; International Headache Genetics Consortium, Saxena R. Habitual sleep disturbances and migraine: a Mendelian randomization study. Ann Clin Transl Neurol. 2020;7(12):2370-2380. doi:10.1002/acn3.51228
Chen M, Li S, Zhu Z, Dai C, Hao X. Investigating the shared genetic architecture and causal relationship between pain and neuropsychiatric disorders. Hum Genet. 2023;142(3):431-443. doi:10.1007/s00439-022-02507-z
Broberg M, Karjalainen J; FinnGen, Ollila HM. Mendelian randomization highlights insomnia as a risk factor for pain diagnoses. Sleep. 2021;44(7):zsab025. doi:10.1093/sleep/zsab025
Gao RC, Sang N, Jia CZ, et al. Association Between Sleep Traits and Rheumatoid Arthritis: A Mendelian Randomization Study. Front Public Health. 2022;10:940161. Published 2022 Jun 30. doi:10.3389/fpubh.2022.940161
Chen J, Zhang J, So HC, et al. Association of Sleep Traits and Heel Bone Mineral Density: Observational and Mendelian Randomization Studies. J Bone Miner Res. 2021;36(11):2184-2192. doi:10.1002/jbmr.4406
Ni J, Zhou W, Cen H, et al. Evidence for causal effects of sleep disturbances on risk for osteoarthritis: a univariable and multivariable Mendelian randomization study. Osteoarthritis Cartilage. 2022;30(3):443-450. doi:10.1016/j.joca.2021.11.021
Irwin M, Clark C, Kennedy B, Christian Gillin J, Ziegler M. Nocturnal catecholamines and immune function in insomniacs, depressed patients, and control subjects. Brain Behav Immun. 2003;17(5):365-372. doi:10.1016/s0889-1591(03)00031-x
Gasbarrino K, Gorgui J, Nauche B, Côté R, Daskalopoulou SS. Circulating adiponectin and carotid intima-media thickness: A systematic review and meta-analysis. Metabolism. 2016;65(7):968-986. doi:10.1016/j.metabol.2016.03.008
Irwin MR, Olmstead R, Carroll JE. Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation. Biol Psychiatry. 2016;80(1):40-52. doi:10.1016/j.biopsych.2015.05.014
Miller MA, Kandala NB, Kumari M, Marmot MG, Cappuccio FP. Relationships between sleep duration and von Willebrand factor, factor VII, and fibrinogen: Whitehall II study. Arterioscler Thromb Vasc Biol. 2010;30(10):2032-2038. doi:10.1161/ATVBAHA.110.206987
Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004;43(4):678-683. doi:10.1016/j.jacc.2003.07.050
Tobaldini E, Fiorelli EM, Solbiati M, Costantino G, Nobili L, Montano N. Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. Nat Rev Cardiol. 2019;16(4):213-224. doi:10.1038/s41569-018-0109-6
Irwin M, Thompson J, Miller C, Gillin JC, Ziegler M. Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications. J Clin Endocrinol Metab. 1999;84(6):1979-1985. doi:10.1210/jcem.84.6.5788
Dettoni JL, Consolim-Colombo FM, Drager LF, et al. Cardiovascular effects of partial sleep deprivation in healthy volunteers. J Appl Physiol (1985). 2012;113(2):232-236. doi:10.1152/japplphysiol.01604.2011
Grandner MA, Buxton OM, Jackson N, Sands-Lincoln M, Pandey A, Jean-Louis G. Extreme sleep durations and increased C-reactive protein: effects of sex and ethnoracial group. Sleep. 2013;36(5):769-779E. Published 2013 May 1. doi:10.5665/sleep.2646
Grandner MA, Sands-Lincoln MR, Pak VM, Garland SN. Sleep duration, cardiovascular disease, and proinflammatory biomarkers. Nat Sci Sleep. 2013;5:93-107. Published 2013 Jul 22. doi:10.2147/NSS.S31063
Ferrie JE, Kivimäki M, Akbaraly TN, et al. Associations between change in sleep duration and inflammation: findings on C-reactive protein and interleukin 6 in the Whitehall II Study. Am J Epidemiol. 2013;178(6):956-961. doi:10.1093/aje/kwt072
Westerlund A, Bellocco R, Sundström J, Adami HO, Åkerstedt T, Trolle Lagerros Y. Sleep characteristics and cardiovascular events in a large Swedish cohort. Eur J Epidemiol. 2013;28(6):463-473. doi:10.1007/s10654-013-9802-2
Okun ML. Biological Consequences of Disturbed Sleep: Important Mediators of Health?. Jpn Psychol Res. 2011;53(2):163-176. doi:10.1111/j.1468-5884.2011.00463.x
Meng L, Zheng Y, Hui R. The relationship of sleep duration and insomnia to risk of hypertension incidence: a meta-analysis of prospective cohort studies. Hypertens Res. 2013;36(11):985-995. doi:10.1038/hr.2013.70
Diemieszczyk I, Głuszyńska P, Wojciak PA, Ładny JR, Razak Hady H. METABOLIC SYNDROME. ETIOLOGY AND PATHOGENESIS. Wiad Lek. 2021;74(10 pt 1):2510-2515.
Bergami M, Fabin N, Cenko E, Bugiardini R, Manfrini O. MicroRNAs as Potential Biomarkers in Coronary Artery Disease [published online ahead of print, 2022 Dec 21]. Curr Top Med Chem. 2022;10.2174/1568026623666221221124530. doi:10.2174/1568026623666221221124530
Henein MY, Vancheri S, Longo G, Vancheri F. The Impact of Mental Stress on Cardiovascular Health-Part II. J Clin Med. 2022;11(15):4405. Published 2022 Jul 28. doi:10.3390/jcm11154405
Wang Y, Li H, Yu XH, Tang CK. CTRP1: A novel player in cardiovascular and metabolic diseases. Cytokine. 2023;164:156162. doi:10.1016/j.cyto.2023.156162
Rodriguez-Hernandez A, Delgado-Machuca M, Guardado-Mendoza R, et al. Doxycycline Prevents Preclinical Atherosclerosis, Pancreatic Islet Loss and Improves Insulin Secretion after Glycemic Stimulation: Preclinical Study in Individuals with a High-Fat Diet. Biomedicines. 2023;11(3):717. Published 2023 Feb 27. doi:10.3390/biomedicines11030717
Li X, Cao Y, Xu X, et al. Sleep Deprivation Promotes Endothelial Inflammation and Atherogenesis by Reducing Exosomal miR-182-5p [published online ahead of print, 2023 Apr 6]. Arterioscler Thromb Vasc Biol. 2023;10.1161/ATVBAHA.123.319026. doi:10.1161/ATVBAHA.123.319026
Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiol. Rev. 2019;99(3):1325-80. doi:10.1152/physrev.00010.2018
Thorkildsen MS, Laugsand LE, Nilsen TIL, et al. Insomnia symptoms and risk of bloodstream infections: prospective data from the prospective population-based HUNT Study, Norway. medRxiv. 2022:2022.05.05.22274704. doi:10.1101/2022.05.05.22274704
Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1):121-137. doi:10.1007/s00424-011-1044-0
Bollinger T, Bollinger A, Skrum L, Dimitrov S, Lange T, Solbach W. Sleep-dependent activity of T cells and regulatory T cells. Clin Exp Immunol. 2009;155(2):231-238. doi:10.1111/j.1365-2249.2008.03822.
Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140(3):774-815. doi:10.1037/a0035302
Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol. 2011;11(9):625-632. Published 2011 Aug 5. doi:10.1038/nri3042
Burgos I, Richter L, Klein T, et al. Increased nocturnal interleukin-6 excretion in patients with primary insomnia: a pilot study. Brain Behav Immun. 2006;20(3):246-253. doi:10.1016/j.bbi.2005.06.007
Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7-11. doi:10.1172/JCI11830
Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1585-1592. doi:10.1164/ajrccm.158.5.9706116
Yang BY, Markevych I, Harris C, et al. High-Sensitivity C-Reactive Protein and Allergic Endpoints in German Adolescents. Int Arch Allergy Immunol. 2019;179(2):152-157. doi:10.1159/000497320
Higuchi S, Nagafuchi Y, Lee SI, Harada T. Influence of light at night on melatonin suppression in children. J Clin Endocrinol Metab. 2014;99(9):3298-3303. doi:10.1210/jc.2014-1629
Chen B, Wang X, Zhao W, Wu J. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res. 2010;29(1):99. Published 2010 Jul 19. doi:10.1186/1756-9966-29-99
Chen B, Ma X, Liu S, Zhao W, Wu J. Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner. Cancer Biol Ther. 2012;13(12):1221-1228. doi:10.4161/cbt.21420
Mochón-Benguigui S, Carneiro-Barrera A, Castillo MJ, Amaro-Gahete FJ. Is Sleep Associated with the S-Klotho Anti-Aging Protein in Sedentary Middle-Aged Adults? The FIT-AGEING Study. Antioxidants (Basel). 2020;9(8):738. Published 2020 Aug 12. doi:10.3390/antiox9080738
Gibson M, Munafò MR, Taylor AE, Treur JL. Evidence for Genetic Correlations and Bidirectional, Causal Effects Between Smoking and Sleep Behaviors. Nicotine Tob Res. 2019;21(6):731-738. doi:10.1093/ntr/nty230
Hecht SS. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol. 2002;3(8):461-469. doi:10.1016/s1470-2045(02)00815-x
Savvidis C, Koutsilieris M. Circadian rhythm disruption in cancer biology. Mol Med. 2012;18(1):1249-1260. Published 2012 Dec 6. doi:10.2119/molmed.2012.00077
Pandi-Perumal SR, Smits M, Spence W, et al. Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):1-11. doi:10.1016/j.pnpbp.2006.06.020
Tamarkin L, Danforth D, Lichter A, et al. Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science. 1982;216(4549):1003-1005. doi:10.1126/science.7079745
Kripke DF, Youngstedt SD, Rex KM, Klauber MR, Elliott JA. Melatonin excretion with affect disorders over age 60. Psychiatry Res. 2003;118(1):47-54. doi:10.1016/s0165-1781(03)00060-x
Du-Quiton J, Wood PA, Burch JB, et al. Actigraphic assessment of daily sleep-activity pattern abnormalities reflects self-assessed depression and anxiety in outpatients with advanced non-small cell lung cancer. Psychooncology. 2010;19(2):180-189. doi:10.1002/pon.1539
Vena C, Parker K, Allen R, Bliwise D, Jain S, Kimble L. Sleep-wake disturbances and quality of life in patients with advanced lung cancer. Oncol Nurs Forum. 2006;33(4):761-769. Published 2006 Jul 1. doi:10.1188/06.ONF.761-769
Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L, Reiter RJ. Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem. 2010;17(36):4462-4481. doi:10.2174/092986710794183015
Sebastián Domingo JJ. Irritable bowel syndrome. Síndrome del intestino irritable. Med Clin (Barc). 2022;158(2):76-81. doi:10.1016/j.medcli.2021.04.029
Lasselin J, Rehman JU, Åkerstedt T, Lekander M, Axelsson J. Effect of long-term sleep restriction and subsequent recovery sleep on the diurnal rhythms of white blood cell subpopulations. Brain Behav Immun. 2015;47:93-99. doi:10.1016/j.bbi.2014.10.004
Godinho-Silva C, Domingues RG, Rendas M, et al. Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis [published correction appears in Nature. 2019 Dec;576(7786):E4]. Nature. 2019;574(7777):254-258. doi:10.1038/s41586-019-1579-3
Cho HJ, Seeman TE, Kiefe CI, Lauderdale DS, Irwin MR. Sleep disturbance and longitudinal risk of inflammation: Moderating influences of social integration and social isolation in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Brain Behav Immun. 2015;46:319-326. doi:10.1016/j.bbi.2015.02.023
Semple JI, Newton JL, Westley BR, May FE. Dramatic diurnal variation in the concentration of the human trefoil peptide TFF2 in gastric juice. Gut. 2001;48(5):648-655. doi:10.1136/gut.48.5.648
Kato K, Murai I, Asai S, et al. Circadian rhythm of melatonin and prostaglandin in modulation of stress-induced gastric mucosal lesions in rats. Aliment Pharmacol Ther. 2002;16 Suppl 2:29-34. doi:10.1046/j.1365-2036.16.s2.11.x
Staudacher HM, Mikocka-Walus A, Ford AC. Common mental disorders in irritable bowel syndrome: pathophysiology, management, and considerations for future randomised controlled trials. Lancet Gastroenterol Hepatol. 2021;6(5):401-410. doi:10.1016/S2468-1253(20)30363-0
Reynolds CF 3rd, O'Hara R. DSM-5 sleep-wake disorders classification: overview for use in clinical practice. Am J Psychiatry. 2013;170(10):1099-1101. doi:10.1176/appi.ajp.2013.13010058
Brodt S, Inostroza M, Niethard N, Born J. Sleep-A brain-state serving systems memory consolidation. Neuron. 2023;111(7):1050-1075. doi:10.1016/j.neuron.2023.03.005
Freeman D, Sheaves B, Goodwin GM, et al. The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis. Lancet Psychiatry. 2017;4(10):749-758. doi:10.1016/S2215-0366(17)30328-0
Burback L, Brémault-Phillips S, Nijdam MJ, McFarlane A, Vermetten E. Treatment of Posttraumatic Stress Disorder: a State-of-the-art Review [published online ahead of print, 2023 Apr 28]. Curr Neuropharmacol. 2023;10.2174/1570159X21666230428091433. doi:10.2174/1570159X21666230428091433
Matenchuk BA, Mandhane PJ, Kozyrskyj AL. Sleep, circadian rhythm, and gut microbiota. Sleep Med Rev. 2020;53:101340. doi:10.1016/j.smrv.2020.101340
Chen J, Wang A, Wang Q. Dysbiosis of the gut microbiome is a risk factor for osteoarthritis in older female adults: a case control study. BMC Bioinformatics. 2021;22(1):299. Published 2021 Jun 3. doi:10.1186/s12859-021-04199-0
Wei J, Zhang C, Zhang Y, et al. Association Between Gut Microbiota and Symptomatic Hand Osteoarthritis: Data From the Xiangya Osteoarthritis Study. Arthritis Rheumatol. 2021;73(9):1656-1662. doi:10.1002/art.41729
Berenbaum F, Meng QJ. The brain-joint axis in osteoarthritis: nerves, circadian clocks and beyond. Nat Rev Rheumatol. 2016;12(9):508-516. doi:10.1038/nrrheum.2016.93
Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ, et al. Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes. Br J Pharmacol. 2018;175(16):3230-3238. doi:10.1111/bph.13898
Hossain FM, Hong Y, Jin Y, Choi J, Hong Y. Physiological and Pathological Role of Circadian Hormones in Osteoarthritis: Dose-Dependent or Time-Dependent?. J Clin Med. 2019;8(9):1415. Published 2019 Sep 8. doi:10.3390/jcm8091415
Scotece M, Mobasheri A. Leptin in osteoarthritis: Focus on articular cartilage and chondrocytes. Life Sci. 2015;140:75-78. doi:10.1016/j.lfs.2015.05.025
Kalinchuk AV, Lu Y, Stenberg D, Rosenberg PA, Porkka-Heiskanen T. Nitric oxide production in the basal forebrain is required for recovery sleep. J Neurochem. 2006;99(2):483-498. doi:10.1111/j.1471-4159.2006.04077.x
Smith MT, Edwards RR, McCann UD, Haythornthwaite JA. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep. 2007;30(4):494-505. doi:10.1093/sleep/30.4.494
Tomim DH, Pontarolla FM, Bertolini JF, et al. The Pronociceptive Effect of Paradoxical Sleep Deprivation in Rats: Evidence for a Role of Descending Pain Modulation Mechanisms. Mol Neurobiol. 2016;53(3):1706-1717. doi:10.1007/s12035-014-9059-0
Haack M, Simpson N, Sethna N, Kaur S, Mullington J. Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications. Neuropsychopharmacology. 2020;45(1):205-216. doi:10.1038/s41386-019-0439-z
Goodin BR, Smith MT, Quinn NB, King CD, McGuire L. Poor sleep quality and exaggerated salivary cortisol reactivity to the cold pressor task predict greater acute pain severity in a non-clinical sample. Biol Psychol. 2012;91(1):36-41. doi:10.1016/j.biopsycho.2012.02.020
Ram A, Pandey HP, Matsumura H, et al. CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats. Brain Res. 1997;751(1):81-89. doi:10.1016/s0006-8993(96)01401-1
Haack M, Scott-Sutherland J, Santangelo G, Simpson NS, Sethna N, Mullington JM. Pain sensitivity and modulation in primary insomnia. Eur J Pain. 2012;16(4):522-533. doi:10.1016/j.ejpain.2011.07.007
Wei Y, Blanken TF, Van Someren EJW. Insomnia Really Hurts: Effect of a Bad Night's Sleep on Pain Increases With Insomnia Severity. Front Psychiatry. 2018;9:377. Published 2018 Aug 28. doi:10.3389/fpsyt.2018.00377
Stoffers D, Altena E, van der Werf YD, et al. The caudate: a key node in the neuronal network imbalance of insomnia?. Brain. 2014;137(Pt 2):610-620. doi:10.1093/brain/awt329

No competing interests reported.

SupplementaryTables.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

The causal role of insomnia in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

Status:

Version 1

Abstract

Figures

Background

Methods

Literature search and inclusion criteria

Data extraction and quality assessment

Statistical analysis

Results

Literature search and study selection

Study quality and description

Diabetes

Diseases of the circulatory system

Neuropsychiatric diseases

Digestive system diseases

Respiratory system diseases

Pain diseases

Musculoskeletal system diseases

Sensitivity analyses

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1