Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles
Open accessAbstract
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.
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Mutations in clock genes such as CRY1, NFIL3 and RORC have been linked to extreme phase delay (delayed sleep-wake phase disorder) in genetic studies of families.
“Mutations in clock genes such as CRY1, NFIL3 and RORC have been linked to extreme phase delay (that is, delayed sleep–wake phase disorder) in genetic studies of families224,225.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [225]
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Kripke, D. F., Nievergelt, C. M., Tranah, G. J., Murray, S. S., Rex, K. M., Grizas, A. P., Hahn, E. K., Lee, H., Kelsoe, J. R., & Kline, L. E. (2013) · Journal of Circadian Rhythms · doi:10.1186/1740-3391-11-3 · Cited by 12 · see citing works
Self-citationVariation and selection in human circadian clock genes
Cade, B. E. (2010) · Surrey Research Insight Open Access (The University of Surrey) · Cited by 2 · see citing works
Flagged first, then by citations
2 of the 92 references couldn’t be matched to a known paper.
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Cited by
Sorted by citations
Rhythms of life: circadian disruption and brain disorders across the lifespan
Logan, R. W., & McClung, C. A. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0088-y · Cited by 713 · see citing works
Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder
Patke, A., Murphy, P. J., Onat, O. E., Krieger, A. C., Özçelik, T., Campbell, S. S., & Young, M. W. (2017) · Cell · doi:10.1016/j.cell.2017.03.027 · Cited by 381 · see citing works
“Nocomparable 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).”
BackgroundResultChronotype and circadian rhythm in bipolar disorder: A systematic review
Melo, M. C. A., Abreu, R. L. C., Linhares Neto, V. B., de Bruin, P. F. C., & de Bruin, V. M. S. (2017) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2016.06.007 · Cited by 324 · see citing works
“Kripke et al., 2014 (8 patients) showed that delayed sleep and “eveningness” were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057).”
BackgroundChronotype, circadian rhythm, and psychiatric disorders: Recent evidence and potential mechanisms
Zou, H.-W., Zhou, H., Yan, R., Yao, Z., & Lu, Q. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.811771 · Cited by 254 · see citing works
“NFIL3 rs2482705 and RORC rs3828057 were inversely associated with evening chronotype (Kripke et al., 2014).”
BackgroundCircadian Rhythm Dysregulation in Bipolar Spectrum Disorders
Alloy, L. B., Ng, T. H., Titone, M. K., & Boland, E. M. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0772-z · Cited by 167 · see citing works
Sleep- and circadian rhythm–associated pathways as therapeutic targets in bipolar disorder
Bellivier, F., Geoffroy, P.-A., Etain, B., & Scott, J. (2015) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2015.1018822 · Cited by 104 · see citing works
“RORA Retinoid-related orphan receptor A [127,128,137] RORB Retinoid-related orphan receptor B [127,128] CSNK1d Casein kinase 1 d [135] CSNK1e Casein kinase 1 e [118,134,135] GSK3b Glycogen synthase kinase 3 b [144,145,148] BHLHB2 Basic helix-loop-helix domain containing, class B, 2 [140] ASMT Acetyl serotonin methyl t…”
BackgroundNon–24-Hour Sleep–Wake Rhythm Disorder in Sighted and Blind Patients
Uchiyama, M., & Lockley, S. W. (2015) · Sleep Medicine Clinics · doi:10.1016/j.jsmc.2015.07.006 · Cited by 77 · see citing works
Takaesu, Y., Inoue, Y., Murakoshi, A., Komada, Y., Otsuka, A., Futenma, K., & Inoue, T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159578 · Cited by 75 · see citing works
“Moreover, there were some common circadian gene polymorphisms among patients with BD, delayed sleep-wake phase disorder, and non-24-hour sleep-wake disorder, which are sub-categories of CRSWD [21].”
BackgroundMicic, G., Lovato, N., Gradisar, M., Burgess, H. J., Ferguson, S. A., & Lack, L. C. (2016) · Journal of Biological Rhythms · doi:10.1177/0748730416650069 · Cited by 61 · see citing works
“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).”
BackgroundARNTL, CLOCK and PER3 polymorphisms – links with chronotype and affective dimensions
Jankowski, K. S., & Dmitrzak‐Węglarz, M. (2017) · Chronobiology International · doi:10.1080/07420528.2017.1343341 · Cited by 57 · see citing works
“…ARNTL (Etain et al., 2014); CLOCK (Barclay et al., 2011; Serretti et al., 2010; Song et al., 2016); PER3 (An et al. 2014; Barclay et al., 2011; Dmitrzak-Węglarz et al., 2016; Etain et al., 2014; Hida et al., 2014; Kripke et al., 2014; Osland et al., 2011); and TIM (Dmitrzak- Węglarz et al., 2016).”
BackgroundInfluentialReitz, C. J., & Martino, T. A. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150706105926 · Cited by 53 · see citing works
“Polymorphisms in other circadian mechanism genes may also be associated with altered sleep timing [79, 80].”
BackgroundPhotoperiodic and circadian bifurcation theories of depression and mania
Kripke, D. F., Elliott, J. A., Welsh, D. K., & Youngstedt, S. D. (2015) · F1000Research · doi:10.12688/f1000research.6444.1 · Cited by 48 · see citing works
Self-citationCircadian Rhythm Disturbances in the Blind
Hartley, S., Dauvilliers, Y. A., & Quera-Salva, M.-A. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0876-9 · Cited by 43 · see citing works
Genetic variants associated with sleep disorders
Kripke, D. F., Kline, L. E., Nievergelt, C. M., Murray, S. S., Shadan, F. F., Dawson, A., Poceta, J. S., CRONIN, J. W., Jamil, S. M., Tranah, G. J., et al. (2014) · Sleep Medicine · doi:10.1016/j.sleep.2014.11.003 · Cited by 39 · see citing works
“A much-studied polymorphism reported to be associated with DSPD, the C3111T SNP in CLOCK (rs1801260) [68], was not a significant correlate of DSPD or morningness–eveningness in the sleep center data [37].”
BackgroundResultSelf-citationGenetic Associations of Chronotype in the Finnish General Population
Maukonen, M., Havulinna, A. S., Männistö, S., Kanerva, N., Salomaa, V. V., & Partonen, T. (2020) · Journal of Biological Rhythms · doi:10.1177/0748730420935328 · Cited by 32 · see citing works
“…solely with continuous sMEQ score (lead SNP rs2440590, with 4 correlated SNPs) and another one solely with single-item chronotype (lead SNP rs2440592, with 4 correlated SNPs) containing a correlated SNP (rs2482705A) that has previously been associated with morning type (Kripke et al., 2014; Suppl.”
BackgroundDisrupted Circadian Rhythms and Substance Use Disorders: A Narrative Review
Sharma, P., & Nelson, R. J. (2024) · Clocks & Sleep · doi:10.3390/clockssleep6030030 · Cited by 25 · see citing works
“Many people are susceptible to environmental factors that disrupt circadian rhythms and cause sleep disturbances, whereas some individuals are genetically prone to circadian misalignment and sleep-related issues [36,37].”
BackgroundДорохов, В. Б., Puchkova, A. N., Олегович, Т. А., Slominsky, P. A., Андреевич, В. В., Ivanov, I. D., Popov, A. V., Nechunaev, V. V., Айзман, Р. И., Владимировна, Б. Е., et al. (2017) · Biological Rhythm Research · doi:10.1080/09291016.2016.1275400 · Cited by 16 · see citing works
“2014), and Californian populations (Kripke et al. 2014).”
BackgroundResultInfluentialDorokhov, V. B., Puchkova, A. N., Taranov, A. O., Slominsky, P. A., Tupitsina, T. V., Ivanov, I. D., Vavilin, V. A., Nechunaev, V. V., Kolomeichuk, S. N., Morozov, A. V., et al. (2018) · Biological Rhythm Research · doi:10.1080/09291016.2017.1390823 · Cited by 11 · see citing works
“The significant associations were most intensively reported for polymorphisms in PER3 (PERiod circadian clock 3; e.g. Ebisawa et al. 2001; Archer et al. 2003; Dijk and Archer 2010; Hida et al. 2014; Johansson et al. 2003; Kripke et al. 2014; Mansour et al. 2017; Parsons et al. 2014; Dorokhov et al. 2017).”
BackgroundInfluentialGenetic and environmental influences on sleep-wake behaviors in adolescence
O’Callaghan, V. S., Hansell, N. K., Guo, W., Carpenter, J. S., Shou, H., Strike, L. T., Crouse, J. J., McAloney, K., McMahon, K. L., Byrne, E. M., et al. (2021) · SLEEP Advances · doi:10.1093/sleepadvances/zpab018 · Cited by 9 · see citing works
Wake Up Time, Light, and Mood in a Population Sample Age 40-64 Years
Endo, T., Kripke, D. F., & Ancoli‐Israel, S. (2015) · Psychiatry Investigation · doi:10.4306/pi.2015.12.2.177 · Cited by 9 · see citing works
Self-citationPutilov, A. A., Dorokhov, V. B., & Poluektov, M. G. (2018) · Chronobiology International · doi:10.1080/07420528.2017.1417314 · Cited by 8 · see citing works
“Besides, negative findings were reported in many other publications (An et al. 2014; Barclay et al. 2011; Kang et al. 2011; Kripke et al. 2014; Mansour et al. 2017; Osland et al. 2011; Perea et al. 2014; Shawa and Roden 2016; Turco et al. 2017; Voinescu and Coogan 2012; etc.).”
ResultUnderstanding the Human Chronotype Research
Sultana, R. (2024) · Annual Research & Review in Biology · doi:10.9734/arrb/2024/v39i92123 · Cited by 3 · see citing works
Putilov, A. A., Ivanov, I. D., Nechunaev, V. V., & Андреевич, В. В. (2017) · Biological Rhythm Research · doi:10.1080/09291016.2017.1354489 · Cited by 2 · see citing works
“On the other hand, we failed to replicate the earlier published findings (Lee et al. 2011; Hida et al. 2014; Kripke et al. 2014) on significant association of this SNP with such widely known trait of the sleep–wake behavior and habits as morning–evening preference (Dorokhov et al. 2017).”
BackgroundResultAstrocytes in the Circadian System: A Promising Target for Mood Disorder Interventions
Liu, P., Li, H., Zhu, Y., Song, S., Kang, L., & Hu, Y. (2026) · Journal of Integrative Neuroscience · doi:10.31083/jin48501 · Cited by 1 · see citing works
Putilov, A. A., Nechunaev, V. V., Ivanov, I. D., Popov, A. V., & Андреевич, В. В. (2017) · Biological Rhythm Research · doi:10.1080/09291016.2017.1319648 · Cited by 1 · see citing works
“…in PER3 gene (rs228697), we failed to replicate the earlier reported findings on its associations with morning–evening preference (Hida et al. 2014; Kripke et al. 2014) possibly due to extremely rare frequency of homozygotes for the minor allele among participants of our study (Dorokhov et al.…”
ResultUeda, H. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727486317.793558651
Genetics of Chronotype and Circadian Rhythm Disorders
Kunorozva, L., & Lane, J. M. (2024) · Springer eBooks · doi:10.1007/978-3-031-62723-1_11
Circadian rhythms in major depressive disorder: mechanistic insights and therapeutic frontiers
Saeed, S., Sang, R., Zhixin, L., Wang, H., Xu, L., Zhang, X., & Hu, S. (2026) · Annals of Medicine · doi:10.1080/07853890.2026.2671594 · Cited by 1 · see citing works
Sleep disorders and cardiovascular diseases
Pan, X., Hussain, Y., & Dar, M. I. (2026) · Trends Open · doi:10.1016/j.treopn.2026.05.013
Barros, C. N., Mayer, R. A., Garcı́a-Borreguero, D., Álvaro, A. R., & Gaspar, L. S. (2026) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2026.102364
- Authors
- Kripke, D. F., Klimecki, W. T., Nievergelt, C. M., Rex, K. M., Murray, S. S., Shekhtman, T., Tranah, G. J., Loving, R. T., Lee, H.-J., Rhee, M. K., Shadan, F. F., Poceta, J. S., Jamil, S. M., Kline, L. E., & Kelsoe, J. R.
- Affiliations
- University of California San Diego (US)
- University of Arizona (US)
- California Pacific Medical Center (US)
- Sharp Mesa Vista Hospital, San Diego, CA, USA.
- Korea University (KR)
- Department of Psychology, Gyeongsang National University, Jinju, Republic of Korea.
- Scripps Clinic (US)
- Corresponding author
- Kripke, Daniel F.
- ORCID
- Venue
- Psychiatry Investigation
- Publisher
- Korean Neuropsychiatric Association
- Published
- 2014
- Volume
- 11
- Issue
- 4
- Pages
- 345
- ISSN
- 1738-3684 (ISSN-L)
- 1976-3026
- PMC
- PMC4225198
- OpenAlex
- W2093662775
- Cited by
- 30
- References
- 92
- Citations by year
- 2026: 4 · 2024: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 8 · 2016: 3 · 2015: 5 · 2014: 1
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- Psychiatry Investigation (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG030474)
- National Heart, Lung, and Blood Institute (R56HL071123, R01HL071123)
- National Institute of Mental Health (R01MH078151, R01MH059567)
- National Institute of Environmental Health Sciences (P30ES006694)
- National Center for Research Resources (UL1RR025774)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- delayed sleep phase syndrome, night owls, bipolar disorder, circadian genes, NFIL3, RORC, BHLHE40, single nucleotide polymorphisms, chronotype, genetic association, melatonin, bright light therapy
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