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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

BALM morningness-eveningness scores are shown for DSPS cases and their controls. Alleles of rs2482705 (A) and Alleles of rs3828057 (B). BALM scores <28 indicate marked eveningness, e.g., DSPS. Scores ≥28 indicate the normal range or greater morningness. The means (blue circles) and 95% confidence intervals (red bars) are shown for homozygotes with the common alleles (left), heterozygotes (center), and for those uncommon homozygotes with the minor alleles (right). For both SNPs, those with 1 or 2 minor alleles (AG or AA) had BALM means outside the confidence limits for the homozygotes (GG) of the common allele, suggesting that minor alleles were associated with dominant protection from DSPS.
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Figure 8: BALM morningness-eveningness scores are shown for DSPS cases and their controls. Alleles of rs2482705 (A) and Alleles of rs3828057 (B). BALM scores <28 indicate marked eveningness, e.g., DSPS. Scores ≥28 indicate the normal range or greater morningness. The means (blue circles) and 95% confidence intervals (red bars) are shown for homozygotes with the common alleles (left), heterozygotes (center), and for those uncommon homozygotes with the minor alleles (right). For both SNPs, those with 1 or 2 minor alleles (AG or AA) had BALM means outside the confidence limits for the homozygotes (GG) of the common allele, suggesting that minor alleles were associated with dominant protection from DSPS.

Mentions: PLINK linear regression of the BALM morningness-eveningness phenotype with a dominant model meta-analysis showed the strongest association with rs2482705 (p=8.6E-05, Bonferroni p=0.053), with 2 nominally significant SNPs in NFIL3 by meta-analysis (Figures 8 and 9). Similar results were obtained with the Horne-Östberg scale (see below). Further nominal association with the BALM phenotype was supported by 6 NFIL3 SNPs in the DSPS-case-control sample and 4 SNPs in the Sleep-Center sample (Supplement 1). Meta-analysis for association of the BALM phenotype with SNPs in RORC was supported only by nominal significance of rs 3828057 (p=0.00189, Bonferroni NS). Although neither rs 2482705 nor rs3828057 were significantly related to bipolar probability scores in the overall European portion of the DSPS-case-control sample (n=466), the minor alleles which appeared protective for DSPS tended to appear somewhat protective for bipolar probability score. Further replication in larger samples would be needed to more accurately assess the strength of these associations.


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)

BALM morningness-eveningness scores are shown for DSPS cases and their controls. Alleles of rs2482705 (A) and Alleles of rs3828057 (B). BALM scores <28 indicate marked eveningness, e.g., DSPS. Scores ≥28 indicate the normal range or greater morningness. The means (blue circles) and 95% confidence intervals (red bars) are shown for homozygotes with the common alleles (left), heterozygotes (center), and for those uncommon homozygotes with the minor alleles (right). For both SNPs, those with 1 or 2 minor alleles (AG or AA) had BALM means outside the confidence limits for the homozygotes (GG) of the common allele, suggesting that minor alleles were associated with dominant protection from DSPS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: BALM morningness-eveningness scores are shown for DSPS cases and their controls. Alleles of rs2482705 (A) and Alleles of rs3828057 (B). BALM scores <28 indicate marked eveningness, e.g., DSPS. Scores ≥28 indicate the normal range or greater morningness. The means (blue circles) and 95% confidence intervals (red bars) are shown for homozygotes with the common alleles (left), heterozygotes (center), and for those uncommon homozygotes with the minor alleles (right). For both SNPs, those with 1 or 2 minor alleles (AG or AA) had BALM means outside the confidence limits for the homozygotes (GG) of the common allele, suggesting that minor alleles were associated with dominant protection from DSPS.
Mentions: PLINK linear regression of the BALM morningness-eveningness phenotype with a dominant model meta-analysis showed the strongest association with rs2482705 (p=8.6E-05, Bonferroni p=0.053), with 2 nominally significant SNPs in NFIL3 by meta-analysis (Figures 8 and 9). Similar results were obtained with the Horne-Östberg scale (see below). Further nominal association with the BALM phenotype was supported by 6 NFIL3 SNPs in the DSPS-case-control sample and 4 SNPs in the Sleep-Center sample (Supplement 1). Meta-analysis for association of the BALM phenotype with SNPs in RORC was supported only by nominal significance of rs 3828057 (p=0.00189, Bonferroni NS). Although neither rs 2482705 nor rs3828057 were significantly related to bipolar probability scores in the overall European portion of the DSPS-case-control sample (n=466), the minor alleles which appeared protective for DSPS tended to appear somewhat protective for bipolar probability score. Further replication in larger samples would be needed to more accurately assess the strength of these associations.

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