0678 Genetic Variants Associated with Dim Light Melatonin Onset in a Delayed Sleep-Wake Phase Disorder Cohort

Abstract Introduction We are conducting a double-blind, randomized, clinical study in Delayed Sleep-Wake Phase Disorder (DSWPD) participants with extensive clinical phenotyping. We evaluated screening Dim Light Melatonin Onset (DLMO) assessments in participants with a DSWPD diagnosis to determine the proportion of participants with and without a circadian delay. Methods Delayed DLMO is DLMO occurring after or within 60 minutes before desired bedtime, and after 22:00. Each DLMO assessment consisted of eight saliva collections performed at five, four, three, two, and one hour before bedtime, at planned bedtime, and one and three hours after bedtime. DLMO assessments were distributed to participants at Visit 1 (screening) and Visit 3 (treatment) with a questionnaire to record planned and actual collection times. Participants were instructed to wear blue-light blocking glasses. The Morningness-Eveningness Questionnaire (MEQ) was also completed by participants at V1 to evaluate circadian and sleep rhythm patterns. DLMO was defined as the clock time when the melatonin concentration exceeded the mean of three low consecutive values, plus twice the standard deviation of these points. Additionally, a sample for whole genome sequencing was collected. Results Forty-seven participants with DSWPD completed the screening DLMO assessment, 38 of which had a DLMO after 22:00 (80.9%). Sub-analyses were conducted on these participants who had delayed DLMO. Within this subset, the average DLMO time was 23:41 and the average MEQ score was significantly lower than those without a circadian delay. Of these 38 participants, 19 had a DLMO time after 00:00. Furthermore, we completed a linear regression analysis on DLMO time in a circadian gene set. The top scoring variant was 3’ UTR rs10181401 in PER2, amongst others detected. Conclusion These initial data indicate that, on average, participants with DSWPD that completed the screening DLMO assessment had delayed DLMO. Further analyses show that half of this subset had significantly delayed DLMO (00:00 or later). This study is currently ongoing and blinded. Further data will be analyzed as more participants enroll. ‘Phase typing’ will be important in further understanding the underlying pathophysiology and in the treatment selection for patients with DSWPD. Support (if any) This work was supported by Vanda Pharmaceuticals Inc.