Limits...
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

Mechanisms by which DSPS-associated SNPs might lead to photoperiodic disturbances. A: Part of the circadian gene network is shown which promotes transcription through pathways leading to E-box activation (green) or which deactivates transcription and E-box promoter action (red). B: The yellow line illustrates normal melatonin secretion commencing shortly before the preferred nocturnal sleep time and terminating about the time of awakening near dawn, so that preferred sleep times and sleepiness normally correspond. The yellow dotted line illustrates how in DSPS, melatonin secretion may become delayed, consequently delaying sleepiness. C: The gene EYA3 reaches a sharp peak in pars tuberalis transcription about 12 hours after darkness onset (solid orange line), but if melatonin is still elevated (in winter or DSPS), the EYA3 peak is largely suppressed (dashed orange line).81 D: After short nights in summer, EYA3 and SIX1 coactivate TEF at a D-box on the TSHβ promoter. TSHβ hybridizes with TSHα, releasing active TSH into 3rd ventricle CSF.81 E: TSH circulates retrograde to promote deiodinase 2 which converts T4 to T3. F: T3 promotes synthesis and release of gonadotropin hormones, implementing summer reproduction and good mood.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4225198&req=5

Figure 10: Mechanisms by which DSPS-associated SNPs might lead to photoperiodic disturbances. A: Part of the circadian gene network is shown which promotes transcription through pathways leading to E-box activation (green) or which deactivates transcription and E-box promoter action (red). B: The yellow line illustrates normal melatonin secretion commencing shortly before the preferred nocturnal sleep time and terminating about the time of awakening near dawn, so that preferred sleep times and sleepiness normally correspond. The yellow dotted line illustrates how in DSPS, melatonin secretion may become delayed, consequently delaying sleepiness. C: The gene EYA3 reaches a sharp peak in pars tuberalis transcription about 12 hours after darkness onset (solid orange line), but if melatonin is still elevated (in winter or DSPS), the EYA3 peak is largely suppressed (dashed orange line).81 D: After short nights in summer, EYA3 and SIX1 coactivate TEF at a D-box on the TSHβ promoter. TSHβ hybridizes with TSHα, releasing active TSH into 3rd ventricle CSF.81 E: TSH circulates retrograde to promote deiodinase 2 which converts T4 to T3. F: T3 promotes synthesis and release of gonadotropin hormones, implementing summer reproduction and good mood.

Mentions: Our findings associating NFIL3 and RORC and a BHLHE40 allele group to DSPS and non-24-hour sleep-wake rhythms suggest polymorphisms in both positive and negative limbs of a primary circadian oscillator feedback loop (Figure 10A). Indeed, since BHLHE40, CRY1, NFIL3, and NR1D1 all themselves have E-boxes in their promoters,56 these genes take part in positive and negative limbs of more extensive feedback loops of such complexity that dozens or even hundreds of additional elements may be involved. Each year we learn of new elements in a circadian oscillatory network which is now suspected to involve hundreds of genes,57 several interlocking transcriptional feedback loops, phosphorylation by several kinases, microRNA effects, regulation of acetylation and deacetylation of DNA and histones, nuclear and cytoplasmic transfer of RNA and proteins, ubiquitin-related metabolism of proteins, redox states, neurotransmitter effects at cell membranes, calcium channels, intercellular coupling, and other complexities.58 The role of specific alleles in non-24-hour rhythms and DSPS could be explored in cell cultures, which display delaying and free-running circadian rhythms related to the donor's phenotype.22,26,59,60 For example, over-expression of BHLHE40 produced phase delays in cell cultures.61 Once the genetic pathways are clarified, the information may be exploited for diagnostic tests and possibly for genetic therapies for DSPS and non-24-hour rhythms.


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)

Mechanisms by which DSPS-associated SNPs might lead to photoperiodic disturbances. A: Part of the circadian gene network is shown which promotes transcription through pathways leading to E-box activation (green) or which deactivates transcription and E-box promoter action (red). B: The yellow line illustrates normal melatonin secretion commencing shortly before the preferred nocturnal sleep time and terminating about the time of awakening near dawn, so that preferred sleep times and sleepiness normally correspond. The yellow dotted line illustrates how in DSPS, melatonin secretion may become delayed, consequently delaying sleepiness. C: The gene EYA3 reaches a sharp peak in pars tuberalis transcription about 12 hours after darkness onset (solid orange line), but if melatonin is still elevated (in winter or DSPS), the EYA3 peak is largely suppressed (dashed orange line).81 D: After short nights in summer, EYA3 and SIX1 coactivate TEF at a D-box on the TSHβ promoter. TSHβ hybridizes with TSHα, releasing active TSH into 3rd ventricle CSF.81 E: TSH circulates retrograde to promote deiodinase 2 which converts T4 to T3. F: T3 promotes synthesis and release of gonadotropin hormones, implementing summer reproduction and good mood.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4225198&req=5

Figure 10: Mechanisms by which DSPS-associated SNPs might lead to photoperiodic disturbances. A: Part of the circadian gene network is shown which promotes transcription through pathways leading to E-box activation (green) or which deactivates transcription and E-box promoter action (red). B: The yellow line illustrates normal melatonin secretion commencing shortly before the preferred nocturnal sleep time and terminating about the time of awakening near dawn, so that preferred sleep times and sleepiness normally correspond. The yellow dotted line illustrates how in DSPS, melatonin secretion may become delayed, consequently delaying sleepiness. C: The gene EYA3 reaches a sharp peak in pars tuberalis transcription about 12 hours after darkness onset (solid orange line), but if melatonin is still elevated (in winter or DSPS), the EYA3 peak is largely suppressed (dashed orange line).81 D: After short nights in summer, EYA3 and SIX1 coactivate TEF at a D-box on the TSHβ promoter. TSHβ hybridizes with TSHα, releasing active TSH into 3rd ventricle CSF.81 E: TSH circulates retrograde to promote deiodinase 2 which converts T4 to T3. F: T3 promotes synthesis and release of gonadotropin hormones, implementing summer reproduction and good mood.
Mentions: Our findings associating NFIL3 and RORC and a BHLHE40 allele group to DSPS and non-24-hour sleep-wake rhythms suggest polymorphisms in both positive and negative limbs of a primary circadian oscillator feedback loop (Figure 10A). Indeed, since BHLHE40, CRY1, NFIL3, and NR1D1 all themselves have E-boxes in their promoters,56 these genes take part in positive and negative limbs of more extensive feedback loops of such complexity that dozens or even hundreds of additional elements may be involved. Each year we learn of new elements in a circadian oscillatory network which is now suspected to involve hundreds of genes,57 several interlocking transcriptional feedback loops, phosphorylation by several kinases, microRNA effects, regulation of acetylation and deacetylation of DNA and histones, nuclear and cytoplasmic transfer of RNA and proteins, ubiquitin-related metabolism of proteins, redox states, neurotransmitter effects at cell membranes, calcium channels, intercellular coupling, and other complexities.58 The role of specific alleles in non-24-hour rhythms and DSPS could be explored in cell cultures, which display delaying and free-running circadian rhythms related to the donor's phenotype.22,26,59,60 For example, over-expression of BHLHE40 produced phase delays in cell cultures.61 Once the genetic pathways are clarified, the information may be exploited for diagnostic tests and possibly for genetic therapies for DSPS and non-24-hour rhythms.

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