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

Kripke DF, Klimecki WT, Nievergelt CM, Rex KM, Murray SS, Shekhtman T, Tranah GJ, Loving RT, Lee HJ, Rhee MK, Shadan FF, Poceta JS, Jamil SM, Kline LE, Kelsoe JR - Psychiatry Investig (2014)

Bottom Line: 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.Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057).Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California, San Diego, CA, USA. ; 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.

No MeSH data available.


Related in: MedlinePlus

Actigraphic record provides an example of a non-24-hour sleep-wake rhythm. This patient wore a wrist activity-light monitor for 4 weeks (starting and ending about 2 PM). On each day (consecutive horizontal lines), the red vertical bars show relative wrist activity, indicating wakefulness. Purple rectangles highlight intervals of predominant inactivity, inferred as sleep with assistance of the patient's sleep log. Vertical yellow bars display the patient's illumination surroundings, plotted on a semi-logarithmic scale of lux (from 1 lux, e.g., full moonlight to 10,000 lux, e.g., bright sunlight.) Note that on many days, the patient experienced little or no daylight. This patient habitually retired to bed an hour or two later each day and awakened correspondingly later (25.4 hr. cycle.) His sleep drifted around the clock, with only minimal pattern irregularities suggesting interactions with the environment. Brief intervals when the actigraph was removed for bathing were not edited.
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Figure 4: Actigraphic record provides an example of a non-24-hour sleep-wake rhythm. This patient wore a wrist activity-light monitor for 4 weeks (starting and ending about 2 PM). On each day (consecutive horizontal lines), the red vertical bars show relative wrist activity, indicating wakefulness. Purple rectangles highlight intervals of predominant inactivity, inferred as sleep with assistance of the patient's sleep log. Vertical yellow bars display the patient's illumination surroundings, plotted on a semi-logarithmic scale of lux (from 1 lux, e.g., full moonlight to 10,000 lux, e.g., bright sunlight.) Note that on many days, the patient experienced little or no daylight. This patient habitually retired to bed an hour or two later each day and awakened correspondingly later (25.4 hr. cycle.) His sleep drifted around the clock, with only minimal pattern irregularities suggesting interactions with the environment. Brief intervals when the actigraph was removed for bathing were not edited.

Mentions: In a severe variation developing from DSPS, sleep and wake arrive later and later, day after day, until a non-24-hour rhythm in sleep-wake may become recognizable (Figure 4). For 37 of the resequenced DSPS participants, the probability of a non-24-hour circadian component could be estimated from actigraphy, besides one bipolar patient known to have had a 21.8 hour non-24-hour rhythm in early adulthood.47 Of the 38, three definitely had non-24-hour circadian rhythms, and one was judged to possibly display a non-24-hour circadian rhythm component. Two homozygous for the associated-minor-allele pattern definitely had non-24-hour rhythms, and the "possible" non-24-hour participant plus the other definite example were heterozygous (p=0.004, exact 2-sided test) (Figure 2, Table 1). The Spearman nonparametric rank order correlation associating the probability of a non-24-hour rhythm (scored 3, 2, 1, or 0) with the number of distinctive-pattern alleles per participant was Rs=0.492 (exact significance p=0.001, one-tailed). Considering the estimated probability of a non-24-hour rhythm, a linear regression model for all ethnicities (genomic inflation factor=1) found association for 9 of the linked SNPs of BHLHE40, including rs34883305, rs34870629, rs74439275, and rs3750275 (all n=37, Beta=0.99, SEBeta=0.18, p=4.58E-09, Bonferroni p=2.95E-06) as well as rs908078 (p=1.53E-07, Bonferroni p=9.87E-05), rs11130215, rs1104976, rs2271566, and rs6790630 (all Bonferroni significant). See also Table 2.


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

Kripke DF, Klimecki WT, Nievergelt CM, Rex KM, Murray SS, Shekhtman T, Tranah GJ, Loving RT, Lee HJ, Rhee MK, Shadan FF, Poceta JS, Jamil SM, Kline LE, Kelsoe JR - Psychiatry Investig (2014)

Actigraphic record provides an example of a non-24-hour sleep-wake rhythm. This patient wore a wrist activity-light monitor for 4 weeks (starting and ending about 2 PM). On each day (consecutive horizontal lines), the red vertical bars show relative wrist activity, indicating wakefulness. Purple rectangles highlight intervals of predominant inactivity, inferred as sleep with assistance of the patient's sleep log. Vertical yellow bars display the patient's illumination surroundings, plotted on a semi-logarithmic scale of lux (from 1 lux, e.g., full moonlight to 10,000 lux, e.g., bright sunlight.) Note that on many days, the patient experienced little or no daylight. This patient habitually retired to bed an hour or two later each day and awakened correspondingly later (25.4 hr. cycle.) His sleep drifted around the clock, with only minimal pattern irregularities suggesting interactions with the environment. Brief intervals when the actigraph was removed for bathing were not edited.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 4: Actigraphic record provides an example of a non-24-hour sleep-wake rhythm. This patient wore a wrist activity-light monitor for 4 weeks (starting and ending about 2 PM). On each day (consecutive horizontal lines), the red vertical bars show relative wrist activity, indicating wakefulness. Purple rectangles highlight intervals of predominant inactivity, inferred as sleep with assistance of the patient's sleep log. Vertical yellow bars display the patient's illumination surroundings, plotted on a semi-logarithmic scale of lux (from 1 lux, e.g., full moonlight to 10,000 lux, e.g., bright sunlight.) Note that on many days, the patient experienced little or no daylight. This patient habitually retired to bed an hour or two later each day and awakened correspondingly later (25.4 hr. cycle.) His sleep drifted around the clock, with only minimal pattern irregularities suggesting interactions with the environment. Brief intervals when the actigraph was removed for bathing were not edited.
Mentions: In a severe variation developing from DSPS, sleep and wake arrive later and later, day after day, until a non-24-hour rhythm in sleep-wake may become recognizable (Figure 4). For 37 of the resequenced DSPS participants, the probability of a non-24-hour circadian component could be estimated from actigraphy, besides one bipolar patient known to have had a 21.8 hour non-24-hour rhythm in early adulthood.47 Of the 38, three definitely had non-24-hour circadian rhythms, and one was judged to possibly display a non-24-hour circadian rhythm component. Two homozygous for the associated-minor-allele pattern definitely had non-24-hour rhythms, and the "possible" non-24-hour participant plus the other definite example were heterozygous (p=0.004, exact 2-sided test) (Figure 2, Table 1). The Spearman nonparametric rank order correlation associating the probability of a non-24-hour rhythm (scored 3, 2, 1, or 0) with the number of distinctive-pattern alleles per participant was Rs=0.492 (exact significance p=0.001, one-tailed). Considering the estimated probability of a non-24-hour rhythm, a linear regression model for all ethnicities (genomic inflation factor=1) found association for 9 of the linked SNPs of BHLHE40, including rs34883305, rs34870629, rs74439275, and rs3750275 (all n=37, Beta=0.99, SEBeta=0.18, p=4.58E-09, Bonferroni p=2.95E-06) as well as rs908078 (p=1.53E-07, Bonferroni p=9.87E-05), rs11130215, rs1104976, rs2271566, and rs6790630 (all Bonferroni significant). See also Table 2.

Bottom Line: 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.Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057).Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of California, San Diego, CA, USA. ; 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.

No MeSH data available.


Related in: MedlinePlus