A PERIOD3 variable number tandem repeat polymorphism modulates melatonin treatment response in delayed sleep-wake phase disorder

Michelle Magee, Tracey L. Sletten, Jade M. Murray, Christopher J. Gordon, Nicole Lovato, Delwyn J. Bartlett, David J. Kennaway, Steven W. Lockley, Leon C. Lack, Ronald R. Grunstein, Simon N. Archer, Shantha M.W. Rajaratnam, Delayed Sleep on Melatonin (DelSoM) Study Group, Gorica Micic, Aeneas Yeo

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7 Citations (Scopus)


We examined whether a polymorphism of the PERIOD3 gene (PER3; rs57875989) modulated the sleep-promoting effects of melatonin in Delayed Sleep-Wake Phase Disorder (DSWPD). One hundred and four individuals (53 males; 29.4 ±10.0 years) with DSWPD and a delayed dim light melatonin onset (DLMO) collected buccal swabs for genotyping (PER34/4 n = 43; PER3 5 allele [heterozygous and homozygous] n = 60). Participants were randomised to placebo or 0.5 mg melatonin taken 1 hour before desired bedtime (or ~1.45 hours before DLMO), with sleep attempted at desired bedtime (4 weeks; 5-7 nights/week). We assessed sleep (diary and actigraphy), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Patient-Reported Outcomes Measurement Information System (PROMIS: Sleep Disturbance, Sleep-Related Impairment), Sheehan Disability Scale (SDS) and Patient- and Clinician-Global Improvement (PGI-C, CGI-C). Melatonin treatment response on actigraphic sleep onset time did not differ between genotypes. For PER34/4 carriers, self-reported sleep onset time was advanced by a larger amount and sleep onset latency (SOL) was shorter in melatonin-treated patients compared to those receiving placebo (P =.008), while actigraphic sleep efficiency in the first third of the sleep episode (SE T1) did not differ. For PER3 5 carriers, actigraphic SOL and SE T1 showed a larger improvement with melatonin (P <.001). Melatonin improved ISI (P =.005), PROMIS sleep disturbance (P <.001) and sleep-related impairment (P =.017), SDS (P =.019), PGI-C (P =.028) and CGI-C (P =.016) in PER34/4 individuals only. Melatonin did not advance circadian phase. Overall, PER34/4 DSWPD patients have a greater response to melatonin treatment. PER3 genotyping may therefore improve DSWPD patient outcomes.

Original languageEnglish
Article numbere12684
Number of pages13
JournalJournal of Pineal Research
Issue number4
Early online date18 Jul 2020
Publication statusPublished - Nov 2020


  • circadian rhythm sleep disorders
  • Delayed Sleep-Wake Phase Disorder
  • melatonin
  • polymorphism
  • variable number tandem repeat


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