0205 Catechol-O-methyltransferase Genotype, but not Dopamine Receptor D2 Genotype, Modulates Slow Wave Sleep

Introduction Slow wave sleep (SWS), a putative marker of sleep homeostasis, robustly increases following total sleep deprivation (TSD). The neurotransmitter dopamine is substantively involved in sleep-wake regulation. Single nucleotide polymorphisms (SNP) in the dopaminergic genes of dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) have been found to alter dopamine availability primarily in the striatum and prefrontal cortex (PFC), respectively. Here, we investigate if these SNPs are associated with changes in SWS at baseline and following TSD. Methods N=105 healthy adults (ages 26.5±5.0; 55 females) completed one of three 4-day/3-night in-laboratory studies with 10h baseline sleep opportunity (22:00–08:00), 38h TSD period, and 10h recovery sleep opportunity. Sleep periods were recorded polysomnographically and visually scored according to AASM criteria. DNA isolated from whole blood was assayed for DRD2 (C957T, rs6277) and COMT (Val158Met, rs4680) genotypes using real-time PCR. For each genotype, SWS duration was analyzed using mixed-effects ANOVA with fixed effects for genotype, night (baseline vs. recovery), and their interaction, controlling for study, and a random effect over subjects on the intercept. Results DRD2 genotypes (25 C/C, 52 C/T, 28 T/T) and COMT genotypes (23 Val/Val, 58 Val/Met, 24 Met/Met) were in Hardy-Weinberg Equilibrium. As expected, SWS was substantially increased during recovery sleep compared to baseline. There was no main effect of DRD2 (F[2,102]=2.78, p=0.07), nor interaction of DRD2 by night (F[2,102]=1.45, p=0.24). However, there was a significant main effect of COMT on SWS duration (F[2,102]=3.20, p=0.04), without interaction of COMT by night (F[2,102]=1.43, p=0.24). Compared to Met allele carriers, Val homozygotes displayed reduced SWS duration during both baseline and recovery sleep. Conclusion The DRD2 T allele is associated with decreased dopamine D2 receptors and decreased dopaminergic signaling in the striatum relative to the C allele. The COMT Val allele is associated with increased enzymatic activity and decreased dopaminergic signaling in the PFC relative to the Met allele. Our results indicate that compared to striatal dopamine, PFC dopamine may be a more prominent mediator of SWS regulation, with less PFC dopamine corresponding to less SWS. This needs to be confirmed in a larger sample. Support (if any) CDMRP W81XWH1610319; USAMRDC W81XWH1810100; ONR N000141310302; NIH R21CA16769; ARO W911NF2210223.