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Psychiatry Investig. 2014 Oct;11(4):345-62. doi: 10.4306/pi.2014.11.4.345. Epub 2014 Oct 20.

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

Author information

1
Department of Psychiatry, University of California, San Diego, CA, USA. ; Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
2
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
3
Department of Psychiatry, University of California, San Diego, CA, USA.
4
Department of Pathology, Center for Advanced Laboratory Medicine, University of California, San Diego, CA, USA.
5
Department of Psychiatry, University of California, San Diego, CA, USA. ; VA San Diego Healthcare System, San Diego, CA, USA.
6
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
7
Sharp Mesa Vista Hospital, San Diego, CA, USA.
8
Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea.
9
Department of Psychology, Gyeongsang National University, Jinju, Republic of Korea.
10
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.

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.

KEYWORDS:

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

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