Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi- cohort multivariable regression and Mendelian randomization analyses

Neil J Goulding, Maxime Bos, Matthew Lee, Rebecca Richmond, Kaitlin H Wade, Diana van Heemst, Raymond Noordam*, Debbie A Lawlor

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Article number69
Number of pages20
JournalBMC Medicine
Issue number1
Early online date18 Mar 2021
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
The HELIUS study is conducted by the Academic Medical Center Amsterdam and the Public Health Service of Amsterdam. Both organisations provided core support for HELIUS. The HELIUS study is also funded by the Dutch Heart Foundation, the Netherlands Organization for Health Research and Development (ZonMw), the European Union (FP-7), and the European Fund for the Integration of non-EU immigrants (EIF). LUMINA is funded by grants obtained from the Netherlands Organization for Health Research and Development (ZonMw; grant nr. 90700217) and VIDI (ZonMw; grant nr. 91711319) (to G.M.T.); The Netherlands Consortium for Systems Biology (NCSB) and the Centre for Medical System Biology (CMSB), both within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) (to A.M.J.M.v.d.M.); the FP7 EU project EUROHEADPAIN (nr. 602633) (to A.M.J.M.v.d.M. and G.M.T.). The infrastructure for the NESDA study ( ) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10000-1002) and financial contributions by participating universities and mental health care organisations (Amsterdam University Medical Centers (location VUmc), GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). Funding for NTR was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); the European Community’s Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC Advanced, 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951). We gratefully acknowledge grant NWO 480-15-001/674: Netherlands Twin Registry Repository: researching the interplay between genome and environment. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing and the Dutch Heart Foundation (2012T008) and the Dutch Cancer Society (NKI-20157737). Metabolomics measurements were funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)-NL (184.021.007) and the JNPD under the project PERADES (grant number 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics). The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Centre, and by the Leiden University, Research Profile Area ‘Vascular and Regenerative Medicine’. The original PROSPER clinical trial was funded by an investigator-initiated grant from Bristol-Myers Squibb, USA. British Heart Foundation through an Intermediate Clinical Research Fellowship to CC (FS/16/45/32359) and a program grant (RG/17/1/32663) to FK. RO1 HL067914 (Principal Investigator: LHL). PE is supported by the UK Dementia Research Institute which receives funding from UK DRI Ltd. funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. PE is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council.

Funding Information:
This research was funded by the British Heart Foundation (AA/18/7/34219), Diabetes UK (17/0005700), and the European Research Council (DevelopObese; 669545), which funds NJG’s salary. KHW is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). NJG, MAL, RCR, KHW, and DAL work in a unit that receives support from the University of Bristol and UK Medical Research Council (MC_UU_00011/6). AD is funded by the Wellcome Trust (206046/Z/17/Z). RM is supported by the President’s PhD scholarship from Imperial College, London. MAL is funded by a UK Medical Research Council PhD studentship (MR/R502340/1). DAL is a UK National Institute for Health Research Senior Investigator (NF-0616-10102).

Publisher Copyright:
© 2021, The Author(s).


  • Mendelian randomization
  • Metabolomics
  • sleep
  • Epidemiology


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