The COMT Val158Met polymorphism related to individual differences in sleep homeostatic responses and physiological sleep responses to chronic PSD. Met/Met subjects showed differentially greater declines across days of PSD in NREM EEG SWE—the putative homeostatic marker of sleep drive—compared with Val/Met and Val/Val subjects, despite comparable baseline declines. Val/Val subjects showed differentially smaller SWS increases and smaller reductions in stage 2 sleep during PSD, had more stage 1 sleep across nights, and a shorter baseline REM sleep latency—all indicative of a lower homeostatic drive. The genotypes demonstrated comparable cumulative decreases in cognitive performance, and increases in subjective and physiological sleepiness and fatigue to PSD, with increasing daily inter-subject variability, and showed no executive function performance differences. The COMT Val158Met polymorphism may be a genetic marker for predicting individual differences in sleep homeostasis and physiology, but not in cognitive and executive function responses, resulting from sleep loss in a healthy, racially-diverse population of men and women. Furthermore, these genotype differences in SWE in response to PSD may extend to psychiatric populations; they may relate to treatment response in depression and schizophrenia and may protect against development and exacerbation of psychosis in these disorders.
Under the phenotypic conditions elicited by PSD, Met/Met
subjects had significantly larger declines in SWE. Moreover, compared with Val/Val
subjects showed significantly less stage 1 sleep and a longer REM sleep latency at baseline and chronic PSD—indicative of a greater sleep homeostatic drive. Since such differences were not observed under basal, fully-rested homeostatic pressure conditions, as was similarly reported in another study 
subjects may possess a greater drive, coupled with a more efficient homeostatic response to sleep loss. Other frequencies, including alpha, which in prior work has shown COMT
genotype differences 
, did not show genotype-dependent differences in our study. This finding suggests that the COMT
Val158Met polymorphism's influence is likely specific to SWA/SWE and is not due to nonspecific effects of the COMT
genotype on EEG-generating mechanisms. Different genes may modulate basal versus evoked homeostatic responses in healthy sleepers; therefore, other markers may influence differential vulnerability in fully-rested conditions.
polymorphism related to individual differences in sleep homeostatic and physiological responses to chronic PSD, contrasting observations in acute TSD 
. This difference may be due to the nature of PSD experiments, in which sleep homeostatic mitigation occurs by partial daily sleep recuperation of sleep 
. Because of this and other reported differences in behavioral and physiological responses to chronic PSD and acute TSD 
, it is possible that specific candidate genes play different roles in the degree of vulnerability and/or resilience to the neurobehavioral and homeostatic effects of these two conditions. In further support of this possibility, we recently found that the PERIOD3
VNTR polymorphism did not relate to individual differences in neurobehavioral performance responses to chronic PSD 
, contrasting data from TSD conditions 
. Future studies should investigate the distinction between PSD and TSD and the manner in which these conditions relate to phenotype-genotype interactions.
homeostatic response to sleep loss may possibly relate to several recent reports of differential responses to treatment in depression as a function of the COMT
Val158Met genotype. For example, this genotype predicted better antidepressant treatment outcome in major depressive disorder 
. Similarly, Benedetti et al. 
found that bipolar Met/Met
patients showed better antidepressant response to the combined chronotherapeutic treatments of sleep deprivation and bright light therapy.
Beyond treatment response, we speculate that the faster dissipation of sleep drive in Met/Met
individuals during exposures to sleep loss may mitigate the development of psychotic features of psychiatric disorders. For example, the Met/Met
genotype has been related to a reduced risk of experiencing psychotic episodes in bipolar disorder 
and has been associated with lower severity of delusions in schizophrenia 
. Whether genotype-related differential responses to sleep loss are important for preventing the development or exacerbation of clinical symptoms is an important area of future investigation in adults with psychiatric disorders.
We found that Met/Met
individuals had higher IQ scores than Val/Val
individuals, as has been reported previously in the literature 
. Even after correcting for this IQ difference, we failed to detect differences across genotypes on a variety of executive functioning or cognitive tasks, in contrast to other reports 
. We also failed to detect differences in PVT performance at baseline or during PSD, in agreement with findings from a study in TSD 
. Similarly, we found no DS performance differences across genotypes, in concurrence with other studies in healthy adults 
. Moreover, a study in TSD conditions reported no genotype differences in the 2-back test or the random number generation task 
and a recent large study in healthy subjects also failed to find genotype differences 
. Our negative results extend meta-analytic results indicating the COMT
Val158Met polymorphism exerts small effects on executive tasks 
, and support the notion that this polymorphism's role is not generalizable to all cognitive tests or to complex cognitive phenotypes 
subjects showed higher sleep homeostatic pressure during PSD, but not poorer cognitive, executive functioning or subjective sleepiness responses. Such a separation has been noted previously whereby the homeostatic sleep responses to chronic PSD or to TSD have not been reflected in waking neurobehavioral or cognitive responses 
. We have yet to identify candidate genes that mediate differential vulnerability to cognitive changes resulting from PSD.
All genotypes showed greater physiological sleepiness, sleep homeostasis, and self-rated sleepiness and fatigue, and poorer cognitive performance across PSD. Thus, PSD produced substantial changes characteristic of cumulative sleep loss, thereby validating our phenotypic approach 
Even though we utilized a large sample size compared to all other candidate gene studies investigating response to sleep loss in healthy adults 
, our findings should be considered preliminary. They serve as a starting point for future—and critical—replication in separate populations.
In addition to the need to replicate our findings, our study has a few limitations. First, we were unable to assess the menstrual cycle phase of our female participants. Second, it is possible that the small but significant genotype difference in REM sleep latency at baseline may affect the relative SWE/SWA values at SR1 and SR5 
. Finally, it is possible that genotype differences in NREM-REM sleep cycle lengths 
may be present during baseline and sleep restriction nights and may influence SWE/SWA hourly values.
In summary, during chronic partial sleep deprivation, Met/Met subjects exhibited faster sleep homeostatic dissipation than Val/Val subjects. The COMT Val158Met polymorphism related to individual differences in sleep homeostatic, but not executive functioning and cognitive responses to chronic PSD, suggesting these measures may be orthogonal and associated with distinct genetic mechanisms. Thus, the COMT Val158Met polymorphism may be a biomarker for predicting differential sleep responses resulting from sleep deprivation in healthy adults and by extension, in various psychiatric populations. We speculate that the sharper dissipation of sleep homeostasis in Met/Met individuals may be protective against the development of psychosis in bipolar depression and schizophrenia, when exposure to sleep loss occurs, and predictive of antidepressant treatment response—these research areas merit further investigation.