Adjusting Your Research Data for Time-of-Day Effects

Written by Nascent Transcript writer Sandra Smieszek

Circadian rhythms affect most aspects of human physiology including sleeping, waking, alertness, optimal treatment regimens, and cognitive and physical performance. A chronotype indicates a person’s circadian rhythm, with morningness and eveningness, which describe the likelihood to sleep at an earlier or later time of night.

The importance of circadian rhythms was highlighted by the 2017 Nobel Prize in Physiology or Medicine, which was awarded to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, for describing the molecular mechanisms controlling circadian rhythms.

Circadian alterations and misalignments occur when people get out of sync from their natural sleep cycles. Such alterations can result in disease and have relevance to metabolic and psychiatric health 1. Evening chronotypes have been associated with greater morbidity, including higher rates of metabolic dysfunction, cardiovascular disease, type II diabetes, and obesity 2. Further, compared to morning types, evening types have significantly increased risk of all-cause mortality, as reported in a recent UK Biobank study 3. With regards to psychiatric health, studies on shift-workers have shown that the eveningness chronotype is associated with increased odds for probable lifetime depression 6.

Aberrations in the clock may also result in classic circadian disorders such as Delayed Phase Sleep Wake Disorder, Advanced Sleep Phase Syndrome, Non-24-Hour Sleep–Wake Syndrome, Irregular Sleep-Wake Rhythm, Jet Lag, and Shift-work Sleep Disorder. In fact, the genetic underpinnings of many of these disorders are linked to variants in clock genes, such as DSPD and CRY1 4. There are also examples of sleep homeostat regulating genes that control the expression of clock genes, such as DEC2 5, highlighting the tight relationship between sleep patterns and circadian rhythms.

Previous studies have estimated the heritability of chronotype to range from 12-21% 7. GWAS studies have shown that significant genetic variation contributes to human chronotypes 2,8. Jones et al. performed a GWAS meta-analysis on chronotype using 697,828 individuals and detected loci enriched for genes involved in circadian regulation, cAMP, glutamate, and insulin signaling pathways. They also found variants within genes expressed in the retina, hindbrain, hypothalamus, and pituitary that were associated with chronotype 2. As more studies take place, it is becoming apparent that variants contributing to chronotype are critical to understanding not only chronotype mechanisms, but also the mechanisms behind certain comorbidities.

A recent study demonstrated that tissue-specific rhythmically expressed human genes can be relevant to circadian medicine 9. Dr. Hogenesch stated, “Whereas gene by environment (GxE) interactions are widely appreciated by the genetics community, gene by circadian (GxC) interactions are not.” Gradually, it is becoming apparent that time-of-day is may have an essential influence on the relationship between genetics and common disease. As such, adjusting for chronotype may be an important consideration for the genetics community to apply in future genetic analyses. This may have particular importance in studies investigating drug dosing 10, where time-of-day is rarely considered but likely has important implications for drug metabolism.

  1. Takahashi, J. S., Hong, H.-K., Ko, C. H. & Mcdearmon, E. L. The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease. doi:10.1038/nrg2430
  2. Jones, S. E. et al. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nat. Commun. 10, 343 (2019).
  3. Knutson, K. L. & von Schantz, M. Associations between chronotype, morbidity and mortality in the UK Biobank cohort. Chronobiol. Int. 35, 1–9 (2018).
  4. Patke, A. et al. Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. Cell 169, 203–215.e13 (2017).
  5. He, Y. et al. The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325, 866–70 (2009).
  6. Norbury, R. Chronotype, depression and hippocampal volume: cross-sectional associations from the UK Biobank. Chronobiol. Int. 1–8 (2019). doi:10.1080/07420528.2019.1578229
  7. Hu, Y. et al. GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person. Nat. Commun. 7, 10448 (2016).
  8. Jansen, P. R. et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nat. Genet. 51, 394–403 (2019).
  9. Ruben, M. D. et al. A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine. Sci. Transl. Med. 10, eaat8806 (2018).
  10. Ruben, M. D., Smith, D. F., FitzGerald, G. A. & Hogenesch, J. B. Dosing Time Matters. bioRxiv 570119 (2019). doi:10.1101/570119

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