Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles.
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.
Department of Psychiatry, University of California, San Diego, CA, USA. ; Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
Daniel F
DF
Kripke
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Walter T
WT
Klimecki
Department of Psychiatry, University of California, San Diego, CA, USA.
Caroline M
CM
Nievergelt
Department of Psychiatry, University of California, San Diego, CA, USA.
Katharine M
KM
Rex
Department of Pathology, Center for Advanced Laboratory Medicine, University of California, San Diego, CA, USA.
Sarah S
SS
Murray
Department of Psychiatry, University of California, San Diego, CA, USA. ; VA San Diego Healthcare System, San Diego, CA, USA.
Tatyana
T
Shekhtman
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Gregory J
GJ
Tranah
Sharp Mesa Vista Hospital, San Diego, CA, USA.
Richard T
RT
Loving
Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea.
Heon-Jeong
HJ
Lee
Department of Psychology, Gyeongsang National University, Jinju, Republic of Korea.
Min Kyu
MK
Rhee
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
Farhad F
FF
Shadan
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
J Steven
JS
Poceta
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
Shazia M
SM
Jamil
Viterbi Family Sleep Center, Scripps Clinic, La Jolla, CA, USA.
Lawrence E
LE
Kline
Department of Psychiatry, University of California, San Diego, CA, USA. ; VA San Diego Healthcare System, San Diego, CA, USA.
John R
JR
Kelsoe
BHLHE40; Bipolar disorder; Delayed sleep phase syndrome; NFIL3; Non-24 hour sleep-wake disorder; RORC