Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. No consistent evidence was observed for effects of chronotype on metabolomic measures. Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h in AMV and 0.15SD in MR) and with isoleucine in MR analyses (0.22SD ). sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD) in AMV and − 0.03SD in MR), higher glycoprotein acetyls (0.08SD in AMV and 0.06SD ), lower total very large HDL particles (− 0.04SD in AMV and − 0.05SD in MR), and lower phospholipids in very large HDL particles (− 0.04SD in AMV and − 0.05SD in MR). We found consistent evidence from AMV and MR analyses for associations of usual vs. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. We used AMV ( N = 17,368) combined with two-sample MR ( N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses
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