Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles

Daniel F. Kripke, Walter Klimecki, Caroline M. Nievergelt, Katharine M. Rex, Sarah S. Murray, Tatyana Shekhtman, Gregory J. Tranah, Richard T. Loving, Heon Jeong Lee, Min Kyu Rhee, Farhad F. Shadan, J. Steven Poceta, Shazia M. Jamil, Lawrence E. Kline, John R. Kelsoe

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness- eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and “eveningness” were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.

Original languageEnglish (US)
Pages (from-to)345-362
Number of pages18
JournalPsychiatry Investigation
Volume11
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Circadian Rhythm Sleep Disorders
Strigiformes
Sleep
Bipolar Disorder
Single Nucleotide Polymorphism
Phenotype
Inborn Genetic Diseases
Polysomnography
Melatonin
Haplotypes
Genes
Meta-Analysis
Case-Control Studies
Comorbidity
Light

Keywords

  • BHLHE40
  • Bipolar disorder
  • Delayed sleep phase syndrome
  • NFIL3
  • Non-24 hour sleep-wake disorder
  • RORC

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Kripke, D. F., Klimecki, W., Nievergelt, C. M., Rex, K. M., Murray, S. S., Shekhtman, T., ... Kelsoe, J. R. (2014). Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles. Psychiatry Investigation, 11(4), 345-362. https://doi.org/10.4306/pi.2014.11.4.345

Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles. / Kripke, Daniel F.; Klimecki, Walter; Nievergelt, Caroline M.; Rex, Katharine M.; Murray, Sarah S.; Shekhtman, Tatyana; Tranah, Gregory J.; Loving, Richard T.; Lee, Heon Jeong; Rhee, Min Kyu; Shadan, Farhad F.; Steven Poceta, J.; Jamil, Shazia M.; Kline, Lawrence E.; Kelsoe, John R.

In: Psychiatry Investigation, Vol. 11, No. 4, 2014, p. 345-362.

Research output: Contribution to journalArticle

Kripke, DF, Klimecki, W, Nievergelt, CM, Rex, KM, Murray, SS, Shekhtman, T, Tranah, GJ, Loving, RT, Lee, HJ, Rhee, MK, Shadan, FF, Steven Poceta, J, Jamil, SM, Kline, LE & Kelsoe, JR 2014, 'Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles', Psychiatry Investigation, vol. 11, no. 4, pp. 345-362. https://doi.org/10.4306/pi.2014.11.4.345
Kripke, Daniel F. ; Klimecki, Walter ; Nievergelt, Caroline M. ; Rex, Katharine M. ; Murray, Sarah S. ; Shekhtman, Tatyana ; Tranah, Gregory J. ; Loving, Richard T. ; Lee, Heon Jeong ; Rhee, Min Kyu ; Shadan, Farhad F. ; Steven Poceta, J. ; Jamil, Shazia M. ; Kline, Lawrence E. ; Kelsoe, John R. / Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles. In: Psychiatry Investigation. 2014 ; Vol. 11, No. 4. pp. 345-362.
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