B3641 - Adolescent insufficient sleep epigenetic changes and the risk of developing AUD and neuropsychiatric comorbidities - 27/10/2020

B number: 
Principal applicant name: 
Luisa de Vivo | Physiology, Pharmacology and Neuroscience, University of Bristol (United Kingdom)
Doretta Caramaschi, PhD, Daniela Franchini, PhD, Michele Bellesi, MD, PhD, Rebecca Richmond, Daniele Marcotulli
Title of project: 
Adolescent insufficient sleep: epigenetic changes and the risk of developing AUD and neuropsychiatric comorbidities
Proposal summary: 

Epidemiological research has shown that adolescents worldwide are chronically sleep deprived due to increased use of technology at night, consumption of caffeinated beverages, as well as more academic and social demands (1-3). Sleep fragmentation and sleep loss have been associated with emotional dysregulation (4), increased psychosis (5), and higher risk-taking behaviours, including substance abuse (6). Adolescents are particularly exposed to the risk of developing substance use disorders (SUDs) and related psychiatric comorbidities (7,8), hence it is particularly important to measure to what extent and how adolescent chronic sleep restriction contributes to the development of such mental disorders. So far, longitudinal analysis using ALSPAC data have found that less total sleep time at age 15 years predicts symptoms and diagnosis of anxiety and depression later in life (9). However, the prospective association between adolescent sleep and development of SUDs has not been explored.
One of the mechanisms through which sleep loss can affect brain function is by inducing epigenetic changes, dynamic modifications that can powerfully regulate gene expression, without changing the heritable genetic sequences. Epigenetic changes in the form of DNA methylation have been associated with both altered sleeping patterns (10,11) and SUDs in adults (12-15). Our goal is to determine whether adolescent sleep patterns predict the risk of developing SUDs later in life and to what extent epigenetic changes are associated with both adolescent chronic sleep restriction and drug consumption. Since, despite recent declines, alcohol remains the substance most widely used by today’s teenagers, this research proposal will focus on alcohol drinking and alcohol use disorders. The results of this analysis will guide future causal experiments to identify the biological mechanisms mediating the consequences of sleep loss and to develop new strategies to reduce alcohol abuse and improve mental health.

1. Crowley SJ, Wolfson AR, Tarokh L, Carskadon MA. An update on adolescent sleep: New evidence informing the perfect storm model. J Adolesc. 2018;67:55-65. doi:10.1016/j.adolescence.2018.06.001
2. Short MA, Weber N, Reynolds C, Coussens S, Carskadon MA. Estimating adolescent sleep need using dose-response modeling. Sleep. 2018;41(4). doi:10.1093/sleep/zsy011
3. Owens J, Adolescent Sleep Working Group, Committee on Adolescence. Insufficient sleep in adolescents and young adults: an update on causes and consequences. Pediatrics. 2014;134(3):e921-932. doi:10.1542/peds.2014-1696
4. Ben Simon E, Vallat R, Barnes CM, Walker MP. Sleep Loss and the Socio-Emotional Brain. Trends Cogn Sci. 2020;24(6):435-450. doi:10.1016/j.tics.2020.02.003
5. Ritter PS, Höfler M, Wittchen H-U, et al. Disturbed sleep as risk factor for the subsequent onset of bipolar disorder--Data from a 10-year prospective-longitudinal study among adolescents and young adults. J Psychiatr Res. 2015;68:76-82. doi:10.1016/j.jpsychires.2015.06.005
6. Short MA, Weber N. Sleep duration and risk-taking in adolescents: A systematic review and meta-analysis. Sleep Med Rev. Published online March 27, 2018. doi:10.1016/j.smrv.2018.03.006
7. Spear LP. Alcohol Consumption in Adolescence: a Translational Perspective. Curr Addict Rep. 2016;3(1):50-61. doi:10.1007/s40429-016-0088-9
8. Saalfield J, Spear L. The ontogeny of ethanol aversion. Physiol Behav. 2016;156:164-170. doi:10.1016/j.physbeh.2016.01.011
9. Orchard F, Gregory AM, Gradisar M, Reynolds S. Self-reported sleep patterns and quality amongst adolescents: cross-sectional and prospective associations with anxiety and depression. J Child Psychol Psychiatry. Published online June 17, 2020. doi:10.1111/jcpp.13288
10. Massart R, Freyburger M, Suderman M, et al. The genome-wide landscape of DNA methylation and hydroxymethylation in response to sleep deprivation impacts on synaptic plasticity genes. Transl Psychiatry. 2014;4(1):e347-e347. doi:10.1038/tp.2013.120
11. Lahtinen A, Puttonen S, Vanttola P, et al. A distinctive DNA methylation pattern in insufficient sleep. Sci Rep. 2019;9(1):1193. doi:10.1038/s41598-018-38009-0
12. Liu C, Marioni RE, Hedman ÅK, et al. A DNA methylation biomarker of alcohol consumption. Mol Psychiatry. 2018;23(2):422-433. doi:10.1038/mp.2016.192
13. Lohoff FW, Roy A, Jung J, et al. Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation. Mol Psychiatry. Published online May 12, 2020. doi:10.1038/s41380-020-0734-4
14. Montalvo-Ortiz JL, Cheng Z, Kranzler HR, Zhang H, Gelernter J. Genomewide Study of Epigenetic Biomarkers of Opioid Dependence in European- American Women. Sci Rep. 2019;9(1):4660. doi:10.1038/s41598-019-41110-7
15. Camilo C, Maschietto M, Vieira HC, et al. Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents. Rev Bras Psiquiatr Sao Paulo Braz 1999. 2019;41(6):485-493. doi:10.1590/1516-4446-2018-0092

Impact of research: 
The results of this analysis will help us determine the role of adolescent sleep patterns in contributing to the development of substance use disorders and related psychiatric comorbidities, informing the public and policy makers on the importance of promoting a correct sleep hygiene to reduce future health problems. The EWAS in adolescents with altered sleep patterns will help identifying possible biomarkers for chronic sleep restrictions and point us towards some of the biological processes mediating the negative effects of poor sleep. These processes will be further investigated in the future by designing causal experiments in animal models that will allow to target separate molecular components and identify their contribution to the development of substance use disorders. Our final goal is to find novel therapeutic strategies to counteract the negative consequences of adolescent sleep impairment, reduce alcohol abuse and improve mental health.
Date proposal received: 
Friday, 23 October, 2020
Date proposal approved: 
Tuesday, 27 October, 2020
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, Statistical methods, Epigenetics