Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses
Authors: Bos Maxime M. , Goulding Neil J. , Lee Matthew A. , Hofman Amy , Bot Mariska , Pool René , Vijfhuizen Lisanne S. , Zhang Xiang , Li Chihua , Mustafa Rima , Neville Matt J. , Li-Gao Ruifang , Trompet Stella , Beekman Marian , Biermasz Nienke R. , Boomsma Dorret I. , de Boer Irene , Christodoulides Constantinos , Dehghan Abbas , van Dijk Ko Willems , Ford Ian , Ghanbari Mohsen , Heijmans Bastiaan T. , Ikram M. Arfan , Jukema J. Wouter , Mook-Kanamori Dennis O. , Karpe Fredrik , Luik Annemarie I. , Lumey L. H. , van den Maagdenberg Arn M. J. M. , Mooijaart Simon P. , de Mutsert Renée , Penninx Brenda W. J. H. , Rensen Patrick C. N. , Richmond Rebecca C. , Rosendaal Frits R. , Sattar Naveed , Schoevers Robert A. , Slagboom P. Eline , Terwindt Gisela M. , Thesing Carisha S. , Wade Kaitlin H. , Wijsman Carolien A. , Willemsen Gonneke , Zwinderman Aeilko H. , van Heemst Diana , Noordam Raymond , Lawlor Deborah A. 
Published: March 2021

Abstract
Background
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. 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.

Methods
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. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. 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. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results
We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (− 0.08 standard deviation (SD)[95% confidence interval (CI) − 0.12, − 0.03] in AMV and − 0.03SD [− 0.07, − 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (− 0.04SD [− 0.08, 0.00] in AMV and − 0.05SD [− 0.09, − 0.02] in MR), and lower phospholipids in very large HDL particles (− 0.04SD [− 0.08, 0.002] in AMV and − 0.05SD [− 0.08, − 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions
Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.