Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles

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.

Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder

“…Based on absence of the PER2 allele in the proband’s affected mother TAUX01 and nieces TAUX08 and TAUX10, the variant was disregarded as a potential DSPD allele. Although several coding variations in PER3 have been associated with late chronotype and DPSD behavior (Archer et al, 2003; Ebisawa et al, 2001; Hida et al, 2014), subsequent studies have often struggled to reproduce these findings, possibly due to limited sample and effect sizes or population-specific correlations in the original studies (Kripke et al, 2014; Osland et al, 2011; Pereira et al, 2005). Among the proposed PER3 polymorphisms, the Val639Gly allele was detected in the TAU11 proband as well as several of our other subjects (both DSPD and normal chronotype controls).…”

“…In humans, rare genetic variations that shorten circadian period are linked to Familial Advanced Sleep Phase Disorder (FASPD), a type of circadian rhythm sleep disorder with habitual sleep times earlier than the societal norm (Hirano et al, 2016; Toh et al, 2001; Xu et al, 2005; Xu et al, 2007). No comparable evidence has yet emerged for DSPD and the association of proposed genetic polymorphisms with late chronotype and DSPD has remained controversial (Kripke et al, 2014). Yet, many classical twin studies have found a strong hereditary component to chronotype preference in the range of 40–50%, arguing for an important role of genetic predisposition to DSPD etiology (Barclay et al, 2010; Hur et al, 1998; Koskenvuo et al, 2007; Vink et al, 2001).…”

Genetic variants associated with sleep disorders

“…Most targeted polymorphisms were selected for relevance to circadian rhythm regulation, but a smaller number were selected based on previous reports of association with sleep disorders [ 31 ]. Previous aspects of our research including detailed assay methods for this genotyping have been presented in prior reports, especially in two reports of associations of these same genotypes with circadian rhythm sleep disorders (delayed sleep phase and non-24-h sleep–wake cycles) and with mood symptoms [ 32 – 37 ]. A few single-nucleotide polymorphisms (SNPs) of special interest were assayed using additional Sequenom, SNPlex, and Taqman assays, as well as some of 27 ancestry-informative markers (AIMS) used to develop multidimensional scale (MDS) dimensions within participants of European ancestry [ 38 ].…”

Circadian Melatonin and Temperature Taus in Delayed Sleep-wake Phase Disorder and Non-24-hour Sleep-wake Rhythm Disorder Patients

“…While these treatment options may not yet be viable, genetic studies and further identification of polymorphisms could point to future treatment (Kripke et al, 2014). While these treatment options may not yet be viable, genetic studies and further identification of polymorphisms could point to future treatment (Kripke et al, 2014).…”