Patke, A.Murphy, P. J.Onat, O. E.Krieger, A. C.Özçelik, T.Campbell, S. S.Young, M. W.2018-04-122018-04-1220170092-8674http://hdl.handle.net/11693/37425Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population. © 2017 Elsevier Inc.EnglishCircadian clockCircadian rhythmDSPDSleepComplementary DNACryptochrome 1MelatoninMessenger RNATranscription factor ARNTLTranscription factor CLOCKArticle10.1016/j.cell.2017.03.027