Genetics and Cognitive Vulnerability to Sleep Deprivation in Healthy Subjects: Interaction of ADORA2A, TNF-α and COMT Polymorphisms

Mégane Erblang, Catherine Drogou, Danielle Gomez-Merino, Arnaud Rabat, Mathias Guillard, Pascal Van Beers, Michael Quiquempoix, Anne Boland, Jean François Deleuze, Robert Olaso, Céline Derbois, Maxime Prost, Rodolphe Dorey, Damien Léger, Claire Thomas, Mounir Chennaoui, Fabien Sauvet, Mégane Erblang, Catherine Drogou, Danielle Gomez-Merino, Arnaud Rabat, Mathias Guillard, Pascal Van Beers, Michael Quiquempoix, Anne Boland, Jean François Deleuze, Robert Olaso, Céline Derbois, Maxime Prost, Rodolphe Dorey, Damien Léger, Claire Thomas, Mounir Chennaoui, Fabien Sauvet

Abstract

Several genetic polymorphisms differentiate between healthy individuals who are more cognitively vulnerable or resistant during total sleep deprivation (TSD). Common metrics of cognitive functioning for classifying vulnerable and resilient individuals include the Psychomotor Vigilance Test (PVT), Go/noGo executive inhibition task, and subjective daytime sleepiness. We evaluated the influence of 14 single-nucleotide polymorphisms (SNPs) on cognitive responses during total sleep deprivation (continuous wakefulness for 38 h) in 47 healthy subjects (age 37.0 ± 1.1 years). SNPs selected after a literature review included SNPs of the adenosine-A2A receptor gene (including the most studied rs5751876), pro-inflammatory cytokines (TNF-α, IL1-β, IL-6), catechol-O-methyl-transferase (COMT), and PER3. Subjects performed a psychomotor vigilance test (PVT) and a Go/noGo-inhibition task, and completed the Karolinska Sleepiness Scale (KSS) every 6 h during TSD. For PVT lapses (reaction time >500 ms), an interaction between SNP and SDT (p < 0.05) was observed for ADORA2A (rs5751862 and rs2236624) and TNF-α (rs1800629). During TSD, carriers of the A allele for ADORA2A (rs5751862) and TNF-α were significantly more impaired for cognitive responses than their respective ancestral G/G genotypes. Carriers of the ancestral G/G genotype of ADORA2A rs5751862 were found to be very similar to the most resilient subjects for PVT lapses and Go/noGo commission errors. Carriers of the ancestral G/G genotype of COMT were close to the most vulnerable subjects. ADORA2A (rs5751862) was significantly associated with COMT (rs4680) (p = 0.001). In conclusion, we show that genetic polymorphisms in ADORA2A (rs5751862), TNF-α (rs1800629), and COMT (rs4680) are involved in creating profiles of high vulnerability or high resilience to sleep deprivation. (NCT03859882).

Keywords: A2A receptor; COMT; IL-6; IL1-β; TNF-α; cognitive responses; genetic polymorphisms; sleep deprivation.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PVT lapses and speed, Go/noGo commission errors, and Karolinska sleepiness (KSS) scores during prolonged wakefulness. Results are median, 25% and 75% range, and individual points. * A significant difference with the values at 2 h of wakefulness.
Figure 2
Figure 2
Effect size (absolute value) for genetic polymorphism mutations. Effect sizes of 0.0099, 0.0588, and 0.1379 were considered small, moderate, and large, respectively.
Figure 3
Figure 3
Average number of PVT lapses across consecutive 6 h intervals during 32 h of prolonged wakefulness for ADORA2A (rs2236624 and rs5751862), TNF-α, and IL1-β polymorphisms. For reference, the average number of lapses on PVT across consecutive 6 h intervals is shown for the most resilient, intermediate, and vulnerable tertiles of our sample without genotypes selection. * A significant difference with the ancestral profile (blue line).
Figure 4
Figure 4
Average commission errors (ratio) on Go/noGo task across consecutive 6 h intervals during 32 h of prolonged wakefulness for COMT, ADORA2A (rs5751862), IL-6, and IL1-β polymorphisms. For reference, the average number of commission errors on Go/noGo across consecutive 6 h intervals is shown for the most resilient, intermediate, and vulnerable tertiles of our sample without genotypes selection. * A significant difference with the ancestral profile (blue line).
Figure 5
Figure 5
Average KSS (Karolinska Sleepiness Scale) scores across consecutive 6 h intervals during 32 h of prolonged wakefulness for ADORA2A (rs5751876), ADA, TNF-α, and IL-6 polymorphisms. For reference, the average KSS score across consecutive 6 h intervals is shown for the most resilient, intermediate, and vulnerable tertiles of our sample without genotype selection. * A significant difference with the ancestral profile (blue line).
Figure 6
Figure 6
Average PVT lapses, Go/noGo commission errors, and KSS score after 2 h and 26 h of prolonged wakefulness for each SNP combination (see Table 4).

References

    1. Connor J., Whitlock G., Norton R., Jackson R. The role of driver sleepiness in car crashes: A systematic review of epidemiological studies. Accid. Anal. Prev. 2001;33:31–41. doi: 10.1016/S0001-4575(00)00013-0.
    1. Goel N., Rao H., Durmer J.S., Dinges D.F. Neurocognitive consequences of sleep deprivation. Semin. Neurol. 2009;29:320–339. doi: 10.1055/s-0029-1237117.
    1. Killgore W.D.S. Progress in Brain Research. Volume 185. Elsevier; Amsterdam, The Netherlands: 2010. Effects of sleep deprivation on cognition; pp. 105–129.
    1. Troxel W.M., Shih R.A., Pedersen E.R., Geyer L., Fisher M.P., Griffin B.A., Haas A.C., Kurz J., Steinberg P.S. Sleep in the military: Promoting healthy sleep among 629 US servicemembers. Rand Health Q. 2015;5:19.
    1. Van Dongen H.P.A., Maislin G., Mullington J.M., Dinges D.F. The cumulative cost of additional wakefulness: Dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep. 2003;26:117–126. doi: 10.1093/sleep/26.2.117.
    1. Basner M., Dinges D.F. Maximizing sensitivity of the psychomotor vigilance test (PVT) to sleep loss. Sleep. 2011;34:581–591. doi: 10.1093/sleep/34.5.581.
    1. Arnal P.J., Sauvet F., Leger D., Van Beers P., Bayon V., Bougard C., Rabat A., Millet G.Y., Chennaoui M. Benefits of sleep extension on sustained attention and sleep pressure before and during total sleep deprivation and recovery. Sleep. 2015;38:1935–1943. doi: 10.5665/sleep.5244.
    1. Van Dongen H.P.A., Maislin G., Dinges D.F. Dealing with inter-individual differences in the temporal dynamics of fatigue and performance: Importance and techniques. Aviat. Space Environ. Med. 2004;75:A147–A154.
    1. Tkachenko O., Dinges D.F. Interindividual variability in neurobehavioral response to sleep loss: A comprehensive review. Neurosci. Biobehav. Rev. 2018;89:29–48. doi: 10.1016/j.neubiorev.2018.03.017.
    1. Rétey J.V., Adam M., Gottselig J.M., Khatami R., Dürr R., Achermann P., Landolt H.-P. Adenosinergic mechanisms contribute to individual differences in sleep deprivation-induced changes in neurobehavioral function and brain rhythmic activity. J. Neurosci. 2006;26:10472–10479. doi: 10.1523/JNEUROSCI.1538-06.2006.
    1. Goel N. Neurobehavioral effects and biomarkers of sleep loss in healthy adults. Curr. Neurol. Neurosci. Rep. 2017;17:89. doi: 10.1007/s11910-017-0799-x.
    1. Satterfield B.C., Stucky B., Landolt H.-P., Van Dongen H.P.A. Unraveling the genetic underpinnings of sleep deprivation-induced impairments in human cognition. Prog. Brain Res. 2019;246:127–158. doi: 10.1016/bs.pbr.2019.03.026.
    1. Porkka-Heiskanen T. Adenosine in sleep and wakefulness. Ann. Med. 1999;31:125–129. doi: 10.3109/07853899908998788.
    1. Logue S.F., Gould T.J. The neural and genetic basis of executive function: Attention, cognitive flexibility, and response inhibition. Pharmacol. Biochem. Behav. 2014;123:45–54. doi: 10.1016/j.pbb.2013.08.007.
    1. Erblang M., Drogou C., Gomez-Merino D., Metlaine A., Boland A., Deleuze J.F., Thomas C., Sauvet F., Chennaoui M. The impact of genetic variations in ADORA2A in the association between caffeine consumption and sleep. Genes. 2019;10:1021. doi: 10.3390/genes10121021.
    1. Bachmann V., Klaus F., Bodenmann S., Schäfer N., Brugger P., Huber S., Berger W., Landolt H.-P. Functional ADA polymorphism increases sleep depth and reduces vigilant attention in humans. Cereb. Cortex. 2012;22:962–970. doi: 10.1093/cercor/bhr173.
    1. Bodenmann S., Hohoff C., Freitag C., Deckert J., Rétey J.V., Bachmann V., Landolt H.-P. Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep eeg after sleep deprivation. Br. J. Pharmacol. 2012;165:1904–1913. doi: 10.1111/j.1476-5381.2011.01689.x.
    1. Reichert C.F., Maire M., Gabel V., Hofstetter M., Viola A.U., Kolodyazhniy V., Strobel W., Goetz T., Bachmann V., Landolt H.-P., et al. The circadian regulation of sleep: Impact of a functional ada-polymorphism and its association to working memory improvements. PLoS ONE. 2014;9:e113734. doi: 10.1371/journal.pone.0113734.
    1. Erblang M., Sauvet F., Drogou C., Quiquempoix M., Van Beers P., Guillard M., Rabat A., Trignol A., Bourrilhon C., Erkel M.-C., et al. Genetic determinants of neurobehavioral responses to caffeine administration during sleep deprivation: A randomized, cross over study (NCT03859882) Genes. 2021;12:555. doi: 10.3390/genes12040555.
    1. Satterfield B.C., Wisor J.P., Field S.A., Schmidt M.A., Van Dongen H.P.A. TNFα G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults. Brain Behav. Immun. 2015;47:66–74. doi: 10.1016/j.bbi.2014.12.009.
    1. Krueger J. The role of cytokines in sleep regulation. Curr. Pharm. Des. 2008;14:3408–3416. doi: 10.2174/138161208786549281.
    1. Knisely M.R., Maserati M., Heinsberg L.W., Shah L.L., Li H., Zhu Y., Ma Y., Graves L.Y., Merriman J.D., Conley Y.P. Symptom science: Advocating for inclusion of functional genetic polymorphisms. Biol. Res. Nurs. 2019;21:349–354. doi: 10.1177/1099800419846407.
    1. Louis E., Franchimont D., Piron A., Gevaert Y., Schaaf-Lafontaine N., Roland S., Mahieu P., Malaise M., De Groote D., Belaiche J. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin. Exp. Immunol. 1998;113:401–406. doi: 10.1046/j.1365-2249.1998.00662.x.
    1. Wilson A.G., Symons J.A., McDowell T.L., McDevitt H.O., Duff G.W. Effects of a polymorphism in the human tumor necrosis factor promoter on transcriptional activation. Proc. Natl. Acad. Sci. USA. 1997;94:3195–3199. doi: 10.1073/pnas.94.7.3195.
    1. Satterfield B.C., Hinson J.M., Whitney P., Schmidt M.A., Wisor J.P., Van Dongen H.P.A. Catechol-O-methyltransferase (COMT) genotype affects cognitive control during total sleep deprivation. Cortex. 2018;99:179–186. doi: 10.1016/j.cortex.2017.11.012.
    1. Holst S.C., Müller T., Valomon A., Seebauer B., Berger W., Landolt H.-P. Functional polymorphisms in dopaminergic genes modulate neurobehavioral and neurophysiological consequences of sleep deprivation. Sci. Rep. 2017;7:45982. doi: 10.1038/srep45982.
    1. Whitney P., Hinson J.M., Satterfield B.C., Grant D.A., Honn K.A., Van Dongen H.P.A. Sleep deprivation diminishes attentional control effectiveness and impairs flexible adaptation to changing conditions. Sci. Rep. 2017;7:16020. doi: 10.1038/s41598-017-16165-z.
    1. Maire M., Reichert C.F., Gabel V., Viola A.U., Strobel W., Krebs J., Landolt H.P., Bachmann V., Cajochen C., Schmidt C. Sleep ability mediates individual differences in the vulnerability to sleep loss: Evidence from a PER3 polymorphism. Cortex. 2014;52:47–59. doi: 10.1016/j.cortex.2013.11.008.
    1. Lo J.C., Groeger J.A., Santhi N., Arbon E.L., Lazar A.S., Hasan S., Von Schantz M., Archer S.N., Dijk D.-J. Effects of partial and acute total sleep deprivation on performance across cognitive domains, individuals and circadian phase. PLoS ONE. 2012;7:e45987. doi: 10.1371/journal.pone.0045987.
    1. Bachmann V., Klein C., Bodenmann S., Schäfer N., Berger W., Brugger P., Landolt H.P. The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state-specificity. Sleep. 2012;35:335–344. doi: 10.5665/sleep.1690.
    1. Grant L.K., Cain S.W., Chang A.-M., Saxena R., Czeisler C.A., Anderson C. Impaired cognitive flexibility during sleep deprivation among carriers of the Brain Derived Neurotrophic Factor (BDNF) Val66Met allele. Behav. Brain Res. 2018;338:51–55. doi: 10.1016/j.bbr.2017.09.025.
    1. Cunha C., Brambilla R., Thomas K.L. A simple role for BDNF in learning and memory? Front. Mol. Neurosci. 2010;3:1. doi: 10.3389/neuro.02.001.2010.
    1. Komar A.A. In: Single Nucleotide Polymorphisms—Methods and Protocols. 2nd ed. Komar A.A., editor. Springer; Berlin/Heidelberg, Germany: 2009.
    1. Drogou C., Sauvet F., Erblang M., Detemmerman L., Derbois C., Erkel M.C., Boland A., Deleuze J.F., Gomez-Merino D., Chennaoui M. Genotyping on blood and buccal cells using loop-mediated isothermal amplification in healthy humans. Biotechnol. Rep. 2020;26:e00468. doi: 10.1016/j.btre.2020.e00468.
    1. Zigmond A.S., Snaith R.P. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 1983;67:361–370. doi: 10.1111/j.1600-0447.1983.tb09716.x.
    1. Johns M.W. A new method for measuring daytime sleepiness: The epworth sleepiness scale. Sleep. 1991;14:540–545. doi: 10.1093/sleep/14.6.540.
    1. Buysse D.J., Reynolds C.F., Monk T.H., Berman S.R., Kupfer D.J. The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–213. doi: 10.1016/0165-1781(89)90047-4.
    1. Horne J.A., Östberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int. J. Chronobiol. 1976;4:97–110.
    1. Åkerstedt T., Gillberg M. Subjective and objective sleepiness in the active individual. Int. J. Neurosci. 1990;52:29–37. doi: 10.3109/00207459008994241.
    1. Rabat A., Gomez-Merino D., Roca-Paixao L., Bougard C., Van Beers P., Dispersyn G., Guillard M., Bourrilhon C., Drogou C., Arnal P.J., et al. Differential kinetics in alteration and recovery of cognitive processes from a chronic sleep restriction in young healthy men. Front. Behav. Neurosci. 2016;10:95. doi: 10.3389/fnbeh.2016.00095.
    1. Cohen J. Statistical Power Analysis for the Behavioral Sciences. Academic Press; Cambridge, MA, USA: 2013.
    1. Richardson J.T.E. Eta squared and partial eta squared as measures of effect size in educational research. Educ. Res. Rev. 2011;6:135–147. doi: 10.1016/j.edurev.2010.12.001.
    1. Solé X., Guinó E., Valls J., Iniesta R., Moreno V. SNPStats: A web tool for the analysis of association studies. Bioinformatics. 2006;15:1928–1929. doi: 10.1093/bioinformatics/btl268.
    1. Drummond S., Paulus M.P., Tapert S.F. Effects of two nights sleep deprivation and two nights recovery sleep on response inhibition. J. Sleep Res. 2006;15:261–265. doi: 10.1111/j.1365-2869.2006.00535.x.
    1. Horn N.R., Dolan M., Elliot R., Deakin J.F.W., Woodruuf P.R.W. Response inhibition and impulsivity: An FMRI study. Neuropsychologia. 2003;41:1959–1966. doi: 10.1016/S0028-3932(03)00077-0.
    1. Childs E., Hohoff C., Deckert J., Xu K., Badner J., De Wit H. Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 2008;33:2791–2800. doi: 10.1038/npp.2008.17.
    1. Hohoff C., Garibotto V., Elmenhorst D., Baffa A., Kroll T., Hoffmann A., Schwarte K., Zhang W., Arolt V., Deckert J., et al. Association of adenosine receptor gene polymorphisms and in vivo adenosine A1 receptor binding in the human brain. Neuropsychopharmacology. 2014;39:2989–2999. doi: 10.1038/npp.2014.150.
    1. Hohoff C., Kroll T., Zhao B., Kerkenberg N., Lang I., Schwarte K., Elmenhorst D., Elmenhorst E.M., Aeschbach D., Zhang W., et al. ADORA2A variation and adenosine A1 receptor availability in the human brain with a focus on anxiety-related brain regions: Modulation by ADORA1 variation. Transl. Psychiatry. 2020;10:406. doi: 10.1038/s41398-020-01085-w.
    1. Huin V., Dhaenens C.M., Homa M., Carvalho K., Buée L., Sablonnière B. Neurogenetics of the human adenosine receptor genes: Genetic structures and involvement in brain diseases. J. Caffeine Adenosine Res. 2019;9:73–88. doi: 10.1089/caff.2019.0011.
    1. Barrett L.W., Fletcher S., Wilton S.D. Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell. Mol. Life Sci. 2012;69:3613–3634. doi: 10.1007/s00018-012-0990-9.
    1. Chennaoui M., Arnal P.J., Drogou C., Leger D., Sauvet F., Gomez-Merino D. Leukocyte expression of type 1 and type 2 purinergic receptors and pro-inflammatory cytokines during total sleep deprivation and/or sleep extension in healthy subjects. Front. Neurosci. 2017;11:240. doi: 10.3389/fnins.2017.00240.
    1. Chennaoui M., Sauvet F., Drogou C., Van Beers P., Langrume C., Guillard M., Gourby B., Bourrilhon C., Florence G., Gomez-Merino D. Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men. Cytokine. 2011;56:318–324. doi: 10.1016/j.cyto.2011.06.002.
    1. Kroeger K.M., Steer J.H., Joyce D.A., Abraham L.J. Effects of stimulus and cell type on the expression of the- 308 tumour necrosis factor promoter polymorphism. Cytokine. 2000;12:110–119. doi: 10.1006/cyto.1999.0529.
    1. Wesensten N.J., Belenky G., Kautz M.A., Thorne D.R., Reichardt R.M., Balkin T.J. Maintaining alertness and performance during sleep deprivation: Modafinil versus caffeine. Psychopharmacology. 2002;159:238–247. doi: 10.1007/s002130100916.
    1. Tunbridge E.M., Harrison P.J. Importance of the COMT gene for sex differences in brain function and predisposition to psychiatric disorders. Curr. Top. Behav. Neurosci. 2011;8:119–140.
    1. Tunbridge E.M., Narajos M., Harrison C.H., Beresford C., Cipriani A., Harrison P.J. Which dopamine polymorphisms are functional? Systematic review and meta-analysis of COMT, DAT, DBH, DDC, DRD1–5, MAOA, MAOB, TH, VMAT1, and VMAT. Biol. Psychiatry. 2019;86:608–620. doi: 10.1016/j.biopsych.2019.05.014.
    1. Vgontzas A.N., Papanicolaou D.A., Bixler E.O., Lotsikas A., Zachman K., Kales A., Prolo P., Wong M.L., Licinio J., Gold P.W., et al. Circadian interleukin-6 secretion and quantity and depth of sleep. J. Clin. Endocrinol. Metab. 1999;84:2603–2607. doi: 10.1210/jcem.84.8.5894.
    1. Smith A.J., D’Aiuto F., Palmen J., Cooper J.A., Samuel J., Thompson S., Sanders J., Donos N., Nibali L., Brull D., et al. Association of serum interleukin-6 concentration with a functional IL6- 6331T> C polymorphism. Clin. Chem. 2008;54:841–850. doi: 10.1373/clinchem.2007.098608.
    1. Rétey J.V., Adam M., Honegger E., Khatami R., Luhmann U.F.O., Jung H.H., Berger W., Landolt H.P. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc. Natl. Acad. Sci. USA. 2005;102:15676–15681. doi: 10.1073/pnas.0505414102.
    1. Sauvet F., Arnal P.J., Tardo-Dino P.-E., Drogou C., Van Beers P., Erblang M., Guillard M., Rabat A., Malgoyre A., Bourrilhon C., et al. Beneficial effects of exercise training on cognitive performances during total sleep deprivation in healthy subjects. Sleep Med. 2020;65:26–35. doi: 10.1016/j.sleep.2019.07.007.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever