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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

Linkage disequilibrium of RORC by ancestry. Linkage (r2) of RORC rs3828057 is shown, compiled and edited from SNAP plots48 for CEU, CHBJPT, and YRI ancestry groups within the 1000 Genome Pilot 1 data base. Linkage with r2 >0.4 ranges in the 3 ancestry groups from the 5' part of RORC to SNPs and genes about 40K downstream to rs3828057. Green arrows show genes in the region with their direction of transcription. RORC binds at RRE transcription factor binding sites on CLOCK, ARNTL, NFIL3, and RORC itself, among others, promoting transcription with complex influences on circadian feedback loops.56 The roles of RORC in immunology have attracted the most interest. No specific role of rs3828057 has been discerned, and considering the substantial linkage to several adjacent genes, further investigation will be needed to confirm that RORC actively influences DSPS.
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Figure 7: Linkage disequilibrium of RORC by ancestry. Linkage (r2) of RORC rs3828057 is shown, compiled and edited from SNAP plots48 for CEU, CHBJPT, and YRI ancestry groups within the 1000 Genome Pilot 1 data base. Linkage with r2 >0.4 ranges in the 3 ancestry groups from the 5' part of RORC to SNPs and genes about 40K downstream to rs3828057. Green arrows show genes in the region with their direction of transcription. RORC binds at RRE transcription factor binding sites on CLOCK, ARNTL, NFIL3, and RORC itself, among others, promoting transcription with complex influences on circadian feedback loops.56 The roles of RORC in immunology have attracted the most interest. No specific role of rs3828057 has been discerned, and considering the substantial linkage to several adjacent genes, further investigation will be needed to confirm that RORC actively influences DSPS.

Mentions: Likewise, rs3828057 in RORC was associated with the DSPS phenotype in the meta-analysis (with OR=0.51, nominal p=1.94E-05, Bonferroni p=0.012). Moreover, this SNP was nominally significant in both the Sleep Center and DSPS-case-control samples, and RORC was significant in the Sleep-Center genewise -set test (p=0.0008)(Supplement 1), but strong linkage disequilibrium extends beyond RORC (Figure 7).


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)

Linkage disequilibrium of RORC by ancestry. Linkage (r2) of RORC rs3828057 is shown, compiled and edited from SNAP plots48 for CEU, CHBJPT, and YRI ancestry groups within the 1000 Genome Pilot 1 data base. Linkage with r2 >0.4 ranges in the 3 ancestry groups from the 5' part of RORC to SNPs and genes about 40K downstream to rs3828057. Green arrows show genes in the region with their direction of transcription. RORC binds at RRE transcription factor binding sites on CLOCK, ARNTL, NFIL3, and RORC itself, among others, promoting transcription with complex influences on circadian feedback loops.56 The roles of RORC in immunology have attracted the most interest. No specific role of rs3828057 has been discerned, and considering the substantial linkage to several adjacent genes, further investigation will be needed to confirm that RORC actively influences DSPS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Linkage disequilibrium of RORC by ancestry. Linkage (r2) of RORC rs3828057 is shown, compiled and edited from SNAP plots48 for CEU, CHBJPT, and YRI ancestry groups within the 1000 Genome Pilot 1 data base. Linkage with r2 >0.4 ranges in the 3 ancestry groups from the 5' part of RORC to SNPs and genes about 40K downstream to rs3828057. Green arrows show genes in the region with their direction of transcription. RORC binds at RRE transcription factor binding sites on CLOCK, ARNTL, NFIL3, and RORC itself, among others, promoting transcription with complex influences on circadian feedback loops.56 The roles of RORC in immunology have attracted the most interest. No specific role of rs3828057 has been discerned, and considering the substantial linkage to several adjacent genes, further investigation will be needed to confirm that RORC actively influences DSPS.
Mentions: Likewise, rs3828057 in RORC was associated with the DSPS phenotype in the meta-analysis (with OR=0.51, nominal p=1.94E-05, Bonferroni p=0.012). Moreover, this SNP was nominally significant in both the Sleep Center and DSPS-case-control samples, and RORC was significant in the Sleep-Center genewise -set test (p=0.0008)(Supplement 1), but strong linkage disequilibrium extends beyond RORC (Figure 7).

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