0211 A 10-week observational research study in individuals with delayed sleep-wake phase disorder (DSWPD) symptoms

Abstract

Abstract Introduction We conducted an observational research study in suspected delayed sleep-wake phase disorder (DSWPD) participants. The objective was to measure sleep-wake patterns and to conduct exploratory genetic analyses to delineate the landscape of DSWPD. Methods We measured the sleep-wake patterns of participants by daily post-sleep diaries for 10 weeks. Participants also completed questionnaires on demographics, medical/surgical history, sleep history, and concomitant medications. Altogether, 119 participants were consented and 76 participants provided samples for whole genome sequencing. Results Sleep diary analysis confirmed delayed sleeping patterns in the study population. Midpoint of sleep was 4:50 AM (SD = 2:06) versus 3:06 AM (SD = 0:59) in controls, a statistically significant difference (t (df) = 6.57 (72.063); p ≤ 0.0001). Mean total sleep time (TST) was 6.88 h (SD = 1.35) versus 7.79 h (SD = 0.56) in controls, a statistically significant difference (t (df) = -5.38 (70.863); p ≤ 0.0001). This effect was driven by shorter participant-reported TST on work nights (6.33 h) versus free nights (7.22 h). Sleep latency was significantly later on work nights than free nights. Altogether 17% of participants reported at least one psychiatric condition.We observed an enrichment of the minisatellite 54bp (1: 7829913-7829966 (GRCh38)) variable number of tandem repeat (VNTR) PER3 rs57875989 4 allele. Significantly higher frequencies of the 4/4 and 4/5 variants were observed when compared to controls (n = 1937; recessive: OR 3.3, CI 2.1177 to 5.4304, p < 0.0001).We analyzed the putative loss-of-function and missense variants. We report on presence of cases with PER3 rs144178755 (NM_001289862:p.T1049), PER3 rs228696 (NM_001289861:p.L835P), and PER2 rs76355956 (NM_022817:p.V197M), among other rare nonsynonymous variants. We observed higher frequency of missense variants in core clock genes when compared to controls. Conclusion Sleep diary data confirmed significantly delayed sleep patterns, with more pronounced results during work nights and larger SDs across all sleep parameters, suggesting more variable sleep patterns. Genetic analysis confirmed these individuals are more likely to harbor variants within their core clock genes with enrichment of the VNTR variant, potentially leading to a pronounced delay in sleep period. Support (If Any) Vanda Pharmaceuticals Inc.