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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

Patterns of associated BHLHE40 SNPs with phenotypes. Rows represent each of the 45 participants resequenced (8 bipolars and 37 DSPS), and columns describe the SNPs. Position is the chromosome-3 base position from assembly GRCH37/hg19. Alleles list the minor allele first, as indicated in the forward DNA strand, and MAF shows the minor allele frequency listed in the UCSC browser 7/6/2013. For the associated SNP pattern: Red shading highlights a minor allele homozygote, and pink shading highlights a minor allele heterozygote for the associated pattern of alleles. Green shading highlights a SNP that was not inferred to be one of the 18 interlinked polymorphisms. Purple highlights the associated allele group (top of columns) and participants with ≥2 such alleles (left columns). *for specification of SNPs without "rs" designations (not appearing in dbSNP) see http://www.ncbi.nlm.nih.gov/nuccore/EF015895, **regarding non-24-hour sleep-wake components or bipolar disorder, symbols in columns 2-3 for a participant indicate. P: possible, L: likely, D: definite, or ?: undetermined.
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Figure 2: Patterns of associated BHLHE40 SNPs with phenotypes. Rows represent each of the 45 participants resequenced (8 bipolars and 37 DSPS), and columns describe the SNPs. Position is the chromosome-3 base position from assembly GRCH37/hg19. Alleles list the minor allele first, as indicated in the forward DNA strand, and MAF shows the minor allele frequency listed in the UCSC browser 7/6/2013. For the associated SNP pattern: Red shading highlights a minor allele homozygote, and pink shading highlights a minor allele heterozygote for the associated pattern of alleles. Green shading highlights a SNP that was not inferred to be one of the 18 interlinked polymorphisms. Purple highlights the associated allele group (top of columns) and participants with ≥2 such alleles (left columns). *for specification of SNPs without "rs" designations (not appearing in dbSNP) see http://www.ncbi.nlm.nih.gov/nuccore/EF015895, **regarding non-24-hour sleep-wake components or bipolar disorder, symbols in columns 2-3 for a participant indicate. P: possible, L: likely, D: definite, or ?: undetermined.

Mentions: We used Sanger resequencing of 15 gene regions to find polymorphisms that might be related to DSPS and phase delay, using 45 DNA samples from research participants with severe DSPS syndromes, non-24-hour rhythms, bipolar disorder, or controls. We identified over 700 polymorphisms in genes of the circadian system.40 A grouping of associated alleles was retrospectively observed in BHLHE40 (previously designated DEC145 or BHLHB2-see EF015895.1).40 The pattern of minor alleles encompassed 17 variably-linked SNPs and one indel among the 29 polymorphisms detected in the 5' promoter, 5' UTR, introns, exons, 3'UTR, and near 3' downstream region (Figure 2). Haploview46 Hapmap 3 data (which include 4 SNPs of the associated allele group) suggest that in Europeans, this loose pattern is interlinked with a network of strong linkage disequilibrium blocks spanning approximately 80 kb both 3' and 5' to BHLHE40. The samples available in the 1000 Genome Pilot 1 suggest a somewhat more limited extent of linkage disequilibrium (Figure 3).


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)

Patterns of associated BHLHE40 SNPs with phenotypes. Rows represent each of the 45 participants resequenced (8 bipolars and 37 DSPS), and columns describe the SNPs. Position is the chromosome-3 base position from assembly GRCH37/hg19. Alleles list the minor allele first, as indicated in the forward DNA strand, and MAF shows the minor allele frequency listed in the UCSC browser 7/6/2013. For the associated SNP pattern: Red shading highlights a minor allele homozygote, and pink shading highlights a minor allele heterozygote for the associated pattern of alleles. Green shading highlights a SNP that was not inferred to be one of the 18 interlinked polymorphisms. Purple highlights the associated allele group (top of columns) and participants with ≥2 such alleles (left columns). *for specification of SNPs without "rs" designations (not appearing in dbSNP) see http://www.ncbi.nlm.nih.gov/nuccore/EF015895, **regarding non-24-hour sleep-wake components or bipolar disorder, symbols in columns 2-3 for a participant indicate. P: possible, L: likely, D: definite, or ?: undetermined.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Patterns of associated BHLHE40 SNPs with phenotypes. Rows represent each of the 45 participants resequenced (8 bipolars and 37 DSPS), and columns describe the SNPs. Position is the chromosome-3 base position from assembly GRCH37/hg19. Alleles list the minor allele first, as indicated in the forward DNA strand, and MAF shows the minor allele frequency listed in the UCSC browser 7/6/2013. For the associated SNP pattern: Red shading highlights a minor allele homozygote, and pink shading highlights a minor allele heterozygote for the associated pattern of alleles. Green shading highlights a SNP that was not inferred to be one of the 18 interlinked polymorphisms. Purple highlights the associated allele group (top of columns) and participants with ≥2 such alleles (left columns). *for specification of SNPs without "rs" designations (not appearing in dbSNP) see http://www.ncbi.nlm.nih.gov/nuccore/EF015895, **regarding non-24-hour sleep-wake components or bipolar disorder, symbols in columns 2-3 for a participant indicate. P: possible, L: likely, D: definite, or ?: undetermined.
Mentions: We used Sanger resequencing of 15 gene regions to find polymorphisms that might be related to DSPS and phase delay, using 45 DNA samples from research participants with severe DSPS syndromes, non-24-hour rhythms, bipolar disorder, or controls. We identified over 700 polymorphisms in genes of the circadian system.40 A grouping of associated alleles was retrospectively observed in BHLHE40 (previously designated DEC145 or BHLHB2-see EF015895.1).40 The pattern of minor alleles encompassed 17 variably-linked SNPs and one indel among the 29 polymorphisms detected in the 5' promoter, 5' UTR, introns, exons, 3'UTR, and near 3' downstream region (Figure 2). Haploview46 Hapmap 3 data (which include 4 SNPs of the associated allele group) suggest that in Europeans, this loose pattern is interlinked with a network of strong linkage disequilibrium blocks spanning approximately 80 kb both 3' and 5' to BHLHE40. The samples available in the 1000 Genome Pilot 1 suggest a somewhat more limited extent of linkage disequilibrium (Figure 3).

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