Association of insomnia, insulin resistance traits, and cardiovascular disease risk: A two-step Mendelian randomization study

Abstract

Aims: Insomnia increases the risk of cardiovascular diseases (CVDs), but whether insulin resistance (IR) or its related traits mediate the underlying associations is unclear. We conducted a two-step two-sample Mendelian randomization (MR) study to address these questions.

Methods and Results: We selected genetic variants of insomnia, IR, and its traits as instrumental variables, whereas summary-level data of five CVDs served as the main outcomes, which were derived from previous genome-wide association studies. In the MR analysis, genetically predicted insomnia symptoms were significantly associated with five CVD risks and six IR-related traits after correcting for multiple tests, whereas genetically predicted IR and its related traits, such as T2DM, TG, and high-density lipoprotein cholesterol (HDL-C), were associated with four CVD risks. In the mediation analysis, we found strong evidence for the mediating effects of IR, TG, HDL-C, and T2DM in the causal pathway from insomnia to four CVDs, except for atrial fibrillation. The multivariable MR analysis provided further evidence supporting the potential mediation effects of IR and its related traits in the causal pathway between insomnia and CVDs.

Conclusions: These results suggest that genetically predicted insomnia symptoms are associated with a higher risk of CVDs, with considerable mediation by IR and T2DM.

Keywords

cardiovascular diseases / insomnia / insulin resistance / mendelian randomization

References

[1] Aquino G, Benz F, Dressle RJ, et al. Towards the neurobiology of insomnia: a systematic review of neuroimaging studies. Sleep Med Rev. 2024;73:101878. https://doi.org/10.1016/j.smrv.2023.101878

[2] Mahmood A, Ray M, Dobalian A, Ward KD, Ahn S. Insomnia symptoms and incident heart failure: a population-based cohort study. Eur Heart J. 2021;42(40):4169-4176. https://doi.org/10.1093/eurheartj/ehab500

[3] Sofi F, Cesari F, Casini A, Macchi C, Abbate R, Gensini GF. Insomnia and risk of cardiovascular disease: a meta-analysis. Eur J Prev Cardiol. 2014;21(1):57-64. https://doi.org/10.1177/2047487312460020

[4] Zheng B, Yu C, Lv J, et al. Insomnia symptoms and risk of cardiovascular diseases among 0.5 million adults: a 10-year cohort. Neurology. 2019;93(23):e2110-e2120. https://doi.org/10.1212/wnl.0000000000008581

[5] Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982-3021. https://doi.org/10.1016/j.jacc.2020.11.010

[6] Huang BH, Duncan MJ, Cistulli PA, Nassar N, Hamer M, Stamatakis E. Sleep and physical activity in relation to all-cause, cardiovascular disease and cancer mortality risk. Br J Sports Med. 2022;56(13):718-724. https://doi.org/10.1136/bjsports-2021-104046

[7] Bertisch SM, Pollock BD, Mittleman MA, et al. Insomnia with objective short sleep duration and risk of incident cardiovascular disease and all-cause mortality: Sleep heart health study. Sleep. 2018;41(6). https://doi.org/10.1093/sleep/zsy047

[8] Ai S, Zhang J, Zhao G, et al. Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK biobank. Eur Heart J. 2021;42(34):3349-3357. https://doi.org/10.1093/eurheartj/ehab170

[9] Yuan S, Mason AM, Burgess S, Larsson SC. Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study. Eur J Epidemiol. 2021;36(4):393-400. https://doi.org/10.1007/s10654-021-00737-5

[10] Zuo B, Yu B, Wang P, et al. The role of circulating fatty acids in mediating the effect of insomnia on heart failure: a two-step, two-sample Mendelian randomization study. Nat Sci Sleep. 2025;17:391-399. https://doi.org/10.2147/nss.s471466

[11] Ai S, Zhang H, Liu J, et al. Investigating the shared genetic architecture between obstructive sleep apnea and sleep-related traits. Sleep Res. 2025;2(4):228-239. https://doi.org/10.1002/slp2.70016

[12] Koopman ADM, Beulens JW, Dijkstra T, et al. Prevalence of insomnia (symptoms) in T2D and association with metabolic parameters and glycemic control: meta-analysis. J Clin Endocrinol Metab. 2020;105(3):614-643. https://doi.org/10.1210/clinem/dgz065

[13] Liu J, Richmond RC, Bowden J, et al. Assessing the causal role of sleep traits on glycated hemoglobin: a Mendelian randomization study. Diabetes Care. 2022;45(4):772-781. https://doi.org/10.2337/dc21-0089

[14] Wang X, Zhao C, Feng H, et al. Associations of insomnia with insulin resistance traits: a cross-sectional and Mendelian randomization study. J Clin Endocrinol Metab. 2023.

[15] Svensson AK, Svensson T, Kitlinski M, et al. Incident diabetes mellitus May explain the association between sleep duration and incident coronary heart disease. Diabetologia. 2018;61(2):331-341. https://doi.org/10.1007/s00125-017-4464-3

[16] Mordi IR, Lumbers RT, Palmer CNA, et al. Type 2 diabetes, metabolic traits, and risk of heart failure: a Mendelian randomization study. Diabetes Care. 2021;44(7):1699-1705. https://doi.org/10.2337/dc20-2518

[17] Didelez V, Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res. 2007;16(4):309-330. https://doi.org/10.1177/0962280206077743

[18] Holmes MV, Ala-Korpela M, Smith GD. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat Rev Cardiol. 2017;14(10):577-590. https://doi.org/10.1038/nrcardio.2017.78

[19] Song Y, Ye T, Roberts LR, Larson NB, Winham SJ. Mendelian randomization in hepatology: a review of principles, opportunities, and challenges. Hepatology. 2025;81(6):1836-1846. https://doi.org/10.1097/hep.0000000000000649

[20] Davey S., Ebrahim S. Mendelian randomization: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1-22. https://doi.org/10.1093/ije/dyg070

[21] Lovegrove CE, Howles SA, Furniss D, Holmes MV. Causal inference in health and disease: a review of the principles and applications of Mendelian randomization. J Bone Min Res. 2024;39(11):1539-1552. https://doi.org/10.1093/jbmr/zjae136

[22] Relton CL, Davey SMITHG. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol. 2012;41(1):161-176. https://doi.org/10.1093/ije/dyr233

[23] Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol. 2021;36(5):465-478. https://doi.org/10.1007/s10654-021-00757-1

[24] Larsson SC, Markus HS. Genetic liability to insomnia and cardiovascular disease risk. Circulation. 2019;140(9):796-798. https://doi.org/10.1161/circulationaha.119.041830

[25] 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. https://doi.org/10.1161/jaha.120.020187

[26] 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. https://doi.org/10.3389/fgene.2020.607865

[27] Soranzo N, Sanna S, Wheeler E, et al. Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways. Diabetes. 2010;59(12):3229-3239. https://doi.org/10.2337/db10-0502

[28] Yuan S, Larsson SC. An atlas on risk factors for type 2 diabetes: a wide-angled Mendelian randomisation study. Diabetologia. 2020;63(11):2359-2371. https://doi.org/10.1007/s00125-020-05253-x

[29] Ai S, Wang X, Wang S, et al. Effects of glycemic traits on left ventricular structure and function: a Mendelian randomization study. Cardiovasc Diabetol. 2022;21(1):109. https://doi.org/10.1186/s12933-022-01540-6

[30] 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. https://doi.org/10.1001/jama.2021.18236

[31] Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. eLife. 2018;7:e34408. https://doi.org/10.7554/elife.34408

[32] Jansen PR, Watanabe K, Stringer S, et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nat Genet. 2019;51(3):394-403. https://doi.org/10.1038/s41588-018-0333-3

[33] Lagou V, MäGI R, Hottenga JJ, et al. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nat Commun. 2021;12(1):24. https://doi.org/10.1038/s41467-020-19366-9

[34] Graham SE, Clarke SL, Wu KH, et al. The power of genetic diversity in genome-wide association studies of lipids. Nature. 2021;600(7890):675-679. https://doi.org/10.1038/s41586-021-04064-3

[35] Xue A, Wu Y, Zhu Z, et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018;9(1):2941. https://doi.org/10.1038/s41467-018-04951-w

[36] Lotta LA, Gulati P, Day FR, et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet. 2017;49(1):17-26. https://doi.org/10.1038/ng.3714

[37] Wang Q, Holmes MV, Davey S, Ala-Korpela M. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diabetes Care. 2017;40(12):1779-1786. https://doi.org/10.2337/dc17-1642

[38] Shah S, Henry A, Roselli C, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun. 2020;11(1):163. https://doi.org/10.1038/s41467-019-13690-5

[39] Van Der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res. 2018;122(3):433-443. https://doi.org/10.1161/circresaha.117.312086

[40] Kurki MI, Karjalainen J, Palta P, et al. FinnGen: unique genetic insights from combining isolated population and national health register data, 2022.

[41] Nielsen JB, Fritsche LG, Zhou W, et al. Genome-wide study of atrial fibrillation identifies seven risk loci and highlights biological pathways and regulatory elements involved in cardiac development. Am J Hum Genet. 2018;102(1):103-115. https://doi.org/10.1016/j.ajhg.2017.12.003

[42] Cheung MW. Comparison of methods for constructing confidence intervals of standardized indirect effects. Behav Res Methods. 2009;41(2):425-438. https://doi.org/10.3758/brm.41.2.425

[43] Bowden J, Davey S, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression. Int J Epidemiol. 2015;44(2):512-525. https://doi.org/10.1093/ije/dyv080

[44] Hemani G, Bowden J, Davey S. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27(R2):R195-r208. https://doi.org/10.1093/hmg/ddy163

[45] Bowden J, Davey S, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304-314. https://doi.org/10.1002/gepi.21965

[46] Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693-698. https://doi.org/10.1038/s41588-018-0099-7

[47] Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755-764. https://doi.org/10.1093/ije/dyr036

[48] Laugsand LE, Vatten LJ, Platou C, Janszky I. Insomnia and the risk of acute myocardial infarction: a population study. Circulation. 2011;124(19):2073-2081. https://doi.org/10.1161/circulationaha.111.025858

[49] Lee HH, Chen YC, Chen JJ, Lo SH, Guo YL, Hu HY. Insomnia and the risk of atrial fibrillation: a population-based cohort study. Acta Cardiol Sin. 2017;33(2):165-172. https://doi.org/10.6515/acs20160611b

[50] Javaheri S, Redline S. Insomnia and risk of cardiovascular disease. Chest. 2017;152(2):435-444. https://doi.org/10.1016/j.chest.2017.01.026

[51] 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. https://doi.org/10.1136/bmjdrc-2021-002510

[52] Liang YY, Chen J, Peng M, et al. Association between sleep duration and metabolic syndrome: linear and nonlinear Mendelian randomization analyses. J Transl Med. 2023;21(1):90. https://doi.org/10.1186/s12967-023-03920-2

[53] Thomas DG, Wei Y, Tall AR. Lipid and metabolic syndrome traits in coronary artery disease: a Mendelian randomization study. J Lipid Res. 2021;62:100044. https://doi.org/10.1194/jlr.p120001000

[54] Jia Y, Wang R, Guo D, et al. Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: a Mendelian randomization study. Nutr Metab Cardiovasc Dis. 2022;32(8):1972-1981. https://doi.org/10.1016/j.numecd.2022.04.019

[55] Li X, Chan JSK, Guan B, et al. Triglyceride-glucose index and the risk of heart failure: evidence from two large cohorts and a Mendelian randomization analysis. Cardiovasc Diabetol. 2022;21(1):229. https://doi.org/10.1186/s12933-022-01658-7

[56] Huang M, Laina-Nicaise LD, Zha L, Tang T, Cheng X. Causal association of type 2 diabetes mellitus and glycemic traits with cardiovascular diseases and lipid traits: a Mendelian randomization study. Front Endocrinol. 2022;13:840579. https://doi.org/10.3389/fendo.2022.840579

[57] Van OORTS, 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. https://doi.org/10.1161/hypertensionaha.120.15761

[58] Harati H, Zanetti D, Rao A, et al. No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia. 2019;62(5):800-804. https://doi.org/10.1007/s00125-019-4836-y

[59] Yang S, Pudasaini R, Zhi H, Wang L. The relationship between blood lipids and risk of atrial fibrillation: univariable and multivariable Mendelian randomization analysis. Nutrients. 2021;14(1):181. https://doi.org/10.3390/nu14010181

[60] Berger M, Solelhac G, Roche F, Heinzer R. Insomnia, a new modifiable risk factor for heart failure? Eur Heart J. 2021;42(40):4177-4179. https://doi.org/10.1093/eurheartj/ehab570

[61] Gao D, Jiao J, Wang Z, et al. The roles of cell-cell and organ-organ crosstalk in the type 2 diabetes mellitus associated inflammatory microenvironment. Cytokine Growth Factor Rev. 2022;66:15-25. https://doi.org/10.1016/j.cytogfr.2022.04.002

[62] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Investig. 2006;116(7):1793-1801. https://doi.org/10.1172/JCI29069

[63] Witkowski M, Weeks TL, Hazen SL. Gut microbiota and cardiovascular disease. Circ Res. 2020;127(4):553-570. https://doi.org/10.1161/circresaha.120.316242

[64] Jiang Z, Zhuo LB, He Y, et al. The gut microbiota-bile acid axis links the positive association between chronic insomnia and cardiometabolic diseases. Nat Commun. 2022;13(1):3002. https://doi.org/10.1038/s41467-022-30712-x

[65] Zhou J, Wu X, Li Z, et al. Alterations in gut microbiota are correlated with serum metabolites in patients with insomnia disorder. Front Cell Infect Microbiol. 2022;12:722662. https://doi.org/10.3389/fcimb.2022.722662

[66] Pang M, Kaufman JS, Platt RW. Studying noncollapsibility of the odds ratio with marginal structural and logistic regression models. Stat Methods Med Res. 2016;25(5):1925-1937. https://doi.org/10.1177/0962280213505804

[67] Greenland S, Pearl J, Robins JM. Confounding and collapsibility in causal inference. Stat Sci. 1999;14(1):29-46. https://doi.org/10.1214/ss/1009211805

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