0035 Melanopsin genetic variants and delayed sleep phenotype – whole genome sequencing analysis

Abstract

Abstract Introduction Melanopsin (OPN4) is a blue light-sensitive opsin-type G-protein coupled receptor. It is highly expressed in photosensitive retinal ganglion cells which mediate responses to light, including regulation of sleep, circadian photoentrainment, and pupillary light response. Mutations in OPN4 were shown to affect responses to light, ultimately affecting the regulation of circadian rhythms and sleep. Previously, we describe a male carrier of the OPN4 missense variant diagnosed with delayed sleep-wake phase disorder (DSWPD), with a consistent recurrent pattern of delayed sleep onset The rs143641898 [NM_033282.4:c.502C>T p.(Arg168Cys)] variant in the OPN4 gene that was shown in a functional study to render the OPN4 protein non-functional. Methods The analysis was conducted on whole genome sequencing samples obtained from patients with a clinical diagnosis of DSWPD. Age and sex-matched samples were used as controls. Results Here we report an enrichment of OPN4 rare coding variants, MAF< 1, in a set of 117 DSWPD samples as compared to 315 healthy controls. This significant enrichment likely implies that other rare pLOFs can similarly contribute to the delayed sleep phenotype. Moreover, we report a significant association of rs rs1079610, a common variant in OPN4 – with delayed bedtime in DSWPD patients. This variant has been previously reported in association with altered pupillary responses. This effect is not seen in a large set of healthy controls without DSWPD diagnosis. Conclusion The OPN4 discussed rare OPN4 variants likely increase the risk of DSWPD via its direct effect on the pathophysiology along the melanopsin axis. This study offers useful insights for the differential diagnosis and ultimately treatment of DSWPD risk in which patients carry pathogenic variants in the OPN4 gene. Support (if any)