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.

Evaluation of Two Circadian Rhythm Questionnaires for Screening for the Delayed Sleep Phase Disorder

OBJECTIVE: Delayed sleep phase disorder (DSPD) is a condition in which patients often fall asleep some hours after midnight and have difficulty waking up in the morning. Circadian chronotype questionnaires such as Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) and Basic Language Morningness (BALM) scale have been used for screening for DSPD. This study was to evaluate these two chronotype questionnaires for screening of DSPD. METHODS: The study samples were 444 DSPD and 438 controls. Cronbach's alpha coefficient was calculated to evaluate for internal consistency. An exploratory factor analysis was conducted using principal-axis factoring. The diagnostic performance of a test was evaluated using Receiver Operating Characteristic (ROC) curve analysis. A discriminant function analysis was also performed. RESULTS: For internal consistency, Cronbach's alpha of 0.898 for BALM was higher than the 0.837 for MEQ, though both have acceptable internal consistency. BALM has better construct validity than the MEQ because some MEQ items measure different dimensions. However, when we evaluated the efficiency of two questionnaires for DSPD diagnosis by using the ROC curve, the BALM was similar to the MEQ. In a discriminant analysis with the BALM to classify the two groups (DSPD vs. normal), 6 items were identified that resulted in good classification accuracy. Upon examination of the classification procedure, 94.2% of the originally grouped cases were classified correctly. CONCLUSION: These findings suggest that the BALM has better psychometric properties than the MEQ in screening and discriminating DSPS.

Self-Reported Sleep Latency in Postmenopausal Women

The aim of this study was to access how self-reported sleep latency (SRSL) was affected by sleep habits, mood, and circadian rhythm in postmenopausal women. Subjects (n=384, 67.9+/-7.7 yr) completed sleep and mood questionnaires, sleep log and actigraphic data. The major urinary melatonin metabolite (6-sulphatoxymelatonin, aMT6s) was assayed in fractional urine specimens for two 24-hr intervals. Although SRSL (26.5+/-24.4 min) and actigraphic sleep latency (ASL; 27.8+/-20.0 min) were correlated (rs=0.361, p<0.001), the short SRSLs tended to be underestimated whereas the long SRSLs tended to be overestimated as compared to ASL. SRSL was positively correlated with the scales of insomnia, mood and hot flash, hypertension, use of anti-hypertensive drugs and the acrophase and the offset of aMT6s. SRSL was negatively correlated with the global assessment of functioning scale in DSM-IV (GAF scale), and light exposure and wrist activity. Multiple linear regression analysis showed that the best-fit model to predict SRSL was light exposure, GAF scale, and use of anti-hypertensive drugs. SRSL may be determined by psychophysiological factors as well as circadian rhythm function. Therapeutic approaches suggested for trouble falling asleep might include increased daylight exposure, improvements in general health, and modification of anti-hypertensive pharmacotherapy.