Expression of core clock genes was linked to circadian disruption and changes in cardiometabolic risk factors in a sex-specific manner among adolescents.
Key Findings
Results
Later sleep midpoint was associated with reduced mid-morning expression of four circadian genes in adolescents.
Study included 203 adolescents (53% females, median age 13.6 years) from the ELEMENT cohort in Mexico City
Per 1-hour increase in sleep midpoint, RORA expression was reduced (log2 fold change [LFC]: -0.190; P=0.001)
RORC expression was reduced (LFC: -0.147; P=0.039), CLOCK expression was reduced (LFC: -0.141; P=0.019), and NR1D2 expression was reduced (LFC: -0.093; P=0.029)
Sleep was assessed via 7-day wrist actigraphy; blood samples collected between 8:00 a.m. and 12:00 p.m. for RNA isolation from blood leukocytes
Analysis adjusted for sleep duration and other potential confounders
Results
NR1D2 expression showed sex-specific associations with metabolic biomarkers over two years.
NR1D2 showed a negative association with fasting glucose among females (β: -0.0012; P=0.020)
NR1D2 showed positive associations with LDL cholesterol (β: 0.0023; P=0.002) and total cholesterol (β: 0.0016; P=0.028) among males
These associations were in opposite directions between sexes, highlighting sex-specific patterns
Follow-up period for cardiometabolic outcome changes was two years
Results
Multiple core clock genes (CRY1, NR1D2, BMAL1, and PER1-3) were associated with changes in metabolic biomarkers over two years in sex-specific patterns.
Cardiometabolic outcomes assessed included changes in adiposity, glucose metabolism, blood pressure, and lipid profiles
Associations were evaluated using linear regression over a two-year follow-up period
Sex-specific patterns were observed across several clock genes, not limited to NR1D2
Study population consisted of 203 adolescents with a median age of 13.6 years
Background
Adolescents are identified as particularly susceptible to circadian disruptors such as delayed sleep onset and social jetlag.
Social jetlag, in addition to sleep midpoint, was examined as a circadian disruptor in the differential gene expression analysis
12 core clock genes were examined in relation to sleep midpoint and social jetlag
The study highlights that circadian disruption effects may have sex-specific influences on gene expression and downstream metabolic outcomes
The authors note that prior evidence linking these disruptors with circadian gene expression and subsequent cardiometabolic risk has been limited
Methods
Blood sample timing was standardized to mid-morning to capture circadian gene expression at a consistent phase.
Fasting venipuncture blood samples were collected between 8:00 a.m. and 12:00 p.m.
RNA was isolated from blood leukocytes and sequenced to determine relative expression of genes
This design allowed assessment of whether circadian phase misalignment (later sleep midpoint) was reflected in altered clock gene expression at a fixed clock time
This research suggests that adolescents who tend to sleep and wake later show lower levels of activity in key 'body clock' genes when their blood is drawn in the morning. The study followed 203 teenagers in Mexico City, measuring their sleep patterns with wrist devices for a week and analyzing gene activity in their blood cells. Four clock genes — RORA, RORC, CLOCK, and NR1D2 — were less active in the morning among teens with later sleep timing, which may mean their biological clocks are out of sync with the time of day when blood was collected.
The study also tracked the teenagers' heart and metabolic health over two years and found that the activity levels of several clock genes were linked to changes in blood sugar, cholesterol, and other metabolic measures — but often differently in males and females. For example, higher NR1D2 gene activity was associated with lower fasting blood glucose in girls, but with higher LDL and total cholesterol in boys. This suggests that the biological pathways connecting sleep timing and metabolic health may differ between sexes during adolescence.
This research matters because it offers a potential biological explanation for why disrupted sleep patterns in teenagers — like staying up late or having very different sleep schedules on weekdays versus weekends — might contribute to long-term heart and metabolic health risks. By identifying specific clock genes that connect sleep timing to metabolic changes, this work points toward possible targets for understanding and eventually addressing circadian-related health risks in young people.
Su D, Goodrich J, Lee J, Dolinoy D, Peterson K, Chervin R, et al.. (2026). Circadian gene expression in adolescents: Associations with concurrent circadian disruption and subsequent changes in cardiometabolic risk measures.. Sleep medicine. https://doi.org/10.1016/j.sleep.2026.108819