rs1801260 — CLOCK 3111T>C (3'UTR)

CLOCK 3111T>C — Your Inner Night Owl Gene

The CLOCK gene (Circadian Locomotor Output Cycles Kaput) encodes the master transcription factor¹¹ transcription factor
A protein that binds to DNA and activates the expression of other genes, in this case driving the ~24-hour circadian rhythm at the heart of the mammalian circadian clock. Working with its partner BMAL1, the CLOCK protein drives rhythmic expression of thousands of genes that govern sleep-wake cycles, hormone secretion, metabolism, and body temperature. The rs1801260 variant — commonly called 3111T>C using the coding strand notation — sits in the 3' untranslated region (3'UTR)²² 3' untranslated region (3'UTR)
The section of mRNA after the stop codon that doesn't code for protein but regulates mRNA stability, localization, and translation efficiency of CLOCK mRNA, where it affects how long the messenger RNA persists in the cell before being degraded.

This was the first human clock gene polymorphism linked to chronotype, identified in a landmark 1998 study³³ landmark 1998 study
Katzenberg D et al. A CLOCK polymorphism associated with human diurnal preference. Sleep, 1998 at Stanford. Carriers of the minor allele scored significantly lower on the Horne-Ostberg morningness-eveningness questionnaire, indicating a shift toward evening preference that was independent of age, sex, and ethnicity.

The Mechanism

The rs1801260 variant falls within a miR-182 binding site⁴⁴ miR-182 binding site
MicroRNA-182 binds to the 3'UTR of CLOCK mRNA and promotes its degradation; the variant allele disrupts this binding in the CLOCK 3'UTR. The minor allele (G on plus strand, C in coding strand notation) disrupts this microRNA interaction site, resulting in increased CLOCK mRNA stability. Cell-based studies using mouse embryonic fibroblasts transfected with the rs1801260 construct showed that the variant allele produces significantly higher levels of CLOCK and downstream Per2 mRNA.

Higher CLOCK protein levels extend the active phase of the transcription-translation feedback loop⁵⁵ transcription-translation feedback loop
The core circadian mechanism: CLOCK/BMAL1 activate PER and CRY genes, whose proteins then inhibit CLOCK/BMAL1, creating a ~24-hour oscillation that defines circadian period length. This molecular shift manifests behaviorally as delayed sleep onset, higher evening activity, and a preference for later bed and wake times.

The Evidence

The original Katzenberg study⁶⁶ original Katzenberg study
Katzenberg D et al. A CLOCK polymorphism associated with human diurnal preference. Sleep, 1998 genotyped 410 adults from a population-based sample and found that C allele carriers had significantly lower Horne-Ostberg scores (shifted toward eveningness), independent of age, sex, and ethnic background.

Benedetti et al. (2007)⁷⁷ Benedetti et al. (2007)
Benedetti F et al. Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression. Am J Med Genet B Neuropsychiatr Genet, 2007 provided objective actimetric data in 39 bipolar depressed inpatients, showing that C allele carriers had 79 minutes later sleep onset and 75 fewer minutes of total sleep compared to T/T homozygotes, with higher evening activity levels — all despite similar depression severity.

The metabolic consequences of this chronotype shift have been well documented. Garaulet et al. (2010)⁸⁸ Garaulet et al. (2010)
Garaulet M et al. CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet. Int J Obes, 2010 studied 1,100 overweight and obese subjects and found that minor allele carriers lost significantly less weight during a Mediterranean diet intervention (P = 0.008), with more carriers being short sleepers (59% vs 41%, P < 0.05).

Garcia-Rios et al. (2014)⁹⁹ Garcia-Rios et al. (2014)
Garcia-Rios A et al. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in metabolic syndrome. Chronobiol Int, 2014 found significant gene-diet interactions in 475 metabolic syndrome patients: after 12 months on a low-fat diet, major allele homozygotes (AA) showed lower insulin and HOMA-IR, while minor allele carriers did not improve as much (interaction P = 0.009 for insulin, P = 0.014 for HOMA-IR).

An association with adult ADHD¹⁰¹⁰ association with adult ADHD
Kissling C et al. A polymorphism at the 3'-untranslated region of the CLOCK gene is associated with adult attention-deficit hyperactivity disorder. Am J Med Genet B, 2008 was found in 143 subjects (P < 0.001), consistent with the known circadian rhythm disruption in ADHD.

It is important to note that large genome-wide association studies of chronotype have not consistently replicated the rs1801260 signal. This may reflect the modest effect size of any single variant and the polygenic nature of chronotype, where hundreds of variants each contribute small effects.

Practical Implications

The CLOCK 3111C allele is not a sleep disorder — it is a common variant that tilts circadian preference toward eveningness. The practical relevance is in recognizing this tendency and structuring daily routines to work with it rather than against it.

For weight management, the evidence suggests that minor allele carriers may benefit from paying particular attention to meal timing, eating the main meal earlier in the day, and avoiding late-night eating. The combination of evening preference and shorter sleep creates a metabolic environment that favors weight gain through altered ghrelin, GLP-1, and insulin dynamics.

Light exposure is the strongest environmental cue for circadian entrainment. Morning bright light exposure (10,000 lux for 20-30 minutes upon waking) can help shift the circadian phase earlier, partially counteracting the genetic evening tendency. Conversely, evening blue light from screens further delays sleep onset in already evening-shifted individuals.

Interactions

The CLOCK 3111C allele interacts with SIRT1 variants to produce additive effects on evening preference and weight loss resistance. Garaulet et al. (2012) showed that carriers of minor alleles at both SIRT1 (rs1467568) and CLOCK (rs1801260) had the strongest evening preference and greatest resistance to weight loss in a behavioral obesity treatment.

CLOCK also interacts functionally with PER2 and PER3 — the period genes that form the negative limb of the circadian feedback loop. While specific gene-gene interaction studies for rs1801260 with PER variants are limited, the biological pathway logic is strong: increased CLOCK expression drives higher PER/CRY production, and variants in PER genes that alter this response could compound the circadian shift.