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

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).

Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with COMT Polymorphism – A Randomized, Crossover Study

“…Our results showed that homozygous carriers of the COMT A allele, resulting in high dopamine levels due to low COMT enzymatic activity, had increased levels of IGF-I in response to prolonged wakefulness beyond 25 h in the PBO condition, whereas IGF-I levels were not increased in carriers of the G allele (either G/A or G/G) resulting in low dopamine levels due to high COMT enzymatic activity. This appears to be consistent with poorer cognitive performance (in the executive go-no-go inhibition task) during prolonged wakefulness in subjects carrying the G/G genotype compared to carriers of the A allele (homozygous and heterozygous), as we have previously shown [8]. We can thus suggest that IGF-I may be involved in sustaining proper cognition during prolonged wakefulness, but that this response would be COMT genotype dependent favoring the A allele carriers, as this polymorphism strongly modulates dopaminergic activity.…”

“…In addition, basic memory scores were lower in Val/Val (or G/G) carriers [21]. Our previous results also indicated a greater cognitive vulnerability to sleep deprivation, as well as sensitivity to CAF intake, in healthy subjects carrying the COMT G/G genotype compared to G/A and A/A genotypes [3, 8]. Taken together, these results suggest that there may be COMT genotype-dependent interindividual variability in IGF-1 levels in response to an experimental condition such as sleep deprivation under CAF administration.…”

“…Participants were free from medical, psychiatric, and sleep disorders. Other exclusion criteria included physical or mental health troubles based on (I) Hospital Anxiety and Depression (HAD) scale, HAD ≥16, (II) significant medical history, (III) Epworth Sleepiness Scale (ESS), ESS >10, (IV) Pittsburg sleep quality index >8, (V) morningness-eveningness questionnaire, <31 or >69, (VI) habitual time in bed per night <6 h [3, 8]. We also excluded subjects younger than 18 years and older than 55 years, with a BMI greater than 30 kg/m 2 , working at night or in shift work or jet lag (>3 time zones) in the previous month, drinking more than 1 glass of alcohol per day, and abusing tobacco.…”

“…The neurotransmitter dopamine contributes to the regulation of different brain functions, including sustained attention and EEG oscillations during wakefulness [5]. On the other hand, several single-nucleotide polymorphisms (SNPs) in dopamine genes are reported to affect cognitive phenotypes [6] during sleep deprivation particularly [7, 8], and robust functional effects were found for the catechol-O-methyltransferase ( COMT ) gene ( Val158Met polymorphism or rs4680) [6, 9]. This enzyme breaks down dopamine mostly in the part of the brain responsible for higher cognitive and executive function (prefrontal cortex).…”

Sleep loss effects on physiological and cognitive responses to systemic environmental hypoxia

“…Finally, several endogenous factors are thought to contribute to the cognitive consequences of severe sleep deficits including the growth hormone/insulin-like growth factor-1 (GH/IGF-1) trophic system, brain-derived neurotrophic factor (BDNF), hormones, and cytokines ( Kreutzmann et al, 2015 ; Chennaoui et al, 2020 ). There are also genotype-dependent interindividual differences in phenotypic neurobehavioral responses to sleep deprivation or restriction ( Bodenmann et al, 2012 ; Erblang et al, 2021b ; Casale and Goel, 2021 ).…”