CLOCK rs1801260 and MTNR1B rs10830963 Polymorphisms Modulate the Association between Cholesterol Levels and Circadian Rhythms in Arctic Residents

Circadian amplitude and CLOCK 3111 polymorphism predict morning leptin in Arctic residents, independent of photoperiod.

This hypothesis-driven study tested whether circadian amplitudes of wrist temperature (WTA), physical activity (PAA), and light exposure measured by actigraphy predicted morning leptin in 64 Arctic residents, and whether the CLOCK 3111 polymorphism (rs1801260) modulated these predictions. Actigraphy measures (circadian amplitudes of WT, PA, and light exposure) and morning leptin concentrations were assessed across seasons with contrasting photoperiods. Multivariate regression models identified leptin predictors. Post-hoc analyses examined WTA-leptin relationships, considering CLOCK 3111 genotype and an exploratory leptin threshold of 13 ng/mL. A multivariate analysis adjusted for the photoperiod revealed significant negative associations between leptin and WTA (β = -0.344), PAA (β = -0.323) and sleep efficiency (β = -0.265) that were retained after further adjustment for age, sex and indigeneity. In the fully adjusted model, a larger normalized amplitude of blue light exposure (NA BLE) was associated with increased WTA (β = 0.256) and lower leptin (β = -0.171). The CLOCK 3111 polymorphism modulated the WTA - leptin relationship, with a strong negative correlation in TT individuals (r = -0.509) and a non-significant trend towards a positive association in CC individuals (r = 0.282), Δr = 0.791, z = 2.31, p = 0.021. In CLOCK 3111 TT individuals, those with a WTA <1°C had significantly higher odds (OR = 3.93, 95% CI: 1.69-9.17, p = 0.0015) and increased relative risk (RR = 2.70, 95% CI: 1.47-4.99, p = 0.0014) of having a morning leptin ≥13 ng/mL, compared to those with a WTA >1.5°C. Overall, the smaller circadian amplitude of WTA and PAA, the lesser sleep quality, and the smaller normalized amplitude of blue light exposure (NA BLE), independently of photoperiod, are associated with elevated leptin in Arctic residents. The CLOCK 3111 polymorphism modulates the WTA-leptin relationship. For CLOCK 3111 TT individuals, a small WTA (<1°C) may identify those at risk of elevated morning leptin (≥13 ng/mL), informing metabolic risk assessment in unique environments.

Impact of Human Melanopsin Gene (OPN4) Polymorphisms (I394T, P10L) on Nocturnal Melatonin and Daily Rhythms in Young Adults

ABSTRACT The present study investigates the impact of two missense SNPs in the human melanopsin gene OPN4 ‐I394T (rs1079610) and P10L (rs2675703)‐ on non‐image‐forming (NIF) physiological and behavioural outputs in healthy young adults under real‐world conditions. Twenty‐five healthy university students were genotyped and analysed under a C‐allele dominant model for I394T and a T‐allele dominant model for P10L. Over 8 days, participants underwent ambulatory monitoring of wrist skin temperature (WT), sleep, activity and light exposure, together with salivary melatonin assessment under five home‐based lighting/time conditions and pupillary light reflex testing. I394T‐C carriers exhibited a phase delay in habitual sleep and WT rhythms, reduced WT amplitude, greater internal desynchronization, and lower nocturnal melatonin concentrations under dim light compared to the TT group. Although behavioural and peripheral rhythms were delayed, circadian phase (DLMO) remained preserved, resulting in an increased phase angle of entrainment. On free days, they also showed greater melatonin suppression despite similar light exposure. In contrast, the P10L‐T allele was not associated with significant differences in ambulatory, hormonal, or pupillary outcomes. Overall, the I394T variant, but not P10L, significantly associates with NIF physiology in young adults, likely by affecting the coupling between environmental light and downstream circadian outputs, independently of circadian phase. These findings also suggest that I394T‐C carriers exhibit features of the circadian phenotype commonly observed in older cohorts, including reduced rhythm robustness and lower melatonin levels, and support a role for this variant in interindividual differences in light sensitivity and circadian function.

[Association of UCP1 rs1800592, UCP2 rs660339, and UCP3 rs1800849 polymorphisms with body mass index and lipid metabolism parameters in the indigenous population of the North of Western Siberia].

Genetic architecture of a Circadian Imbalance Index: genome-wide association, phenome-wide association, and Mendelian randomisation analyses

Summary Background Circadian disruption affects multiple aspects of human health, but the genetic architecture of individual susceptibility remains unclear. We examined the genetics of the Circadian Imbalance Index (CII), an additive 0–5 score combining evening chronotype, short/long sleep, high neuroticism, atypical caffeinated coffee intake, and low vitamin D. Methods We ran a genome-wide association study (GWAS) of CII in 312,935 European-ancestry UK Biobank participants, compared signals with component-specific and leave-one-component-out (LOCO) GWASs, and tested sex and shift work interactions. CII polygenic score (PRS) PheWAS analyses were evaluated in Mass General Brigham Biobank (N = 50,908) and All of US (N = 98,182), with component-weighted PRS sensitivity analyses. Replication was assessed in Nurses’ Health Study II women (N = 11,344). We estimated genetic correlations and performed bidirectional two-sample Mendelian randomisation (MR) with MR-Egger, weighted median and LOCO sensitivity analyses. Findings We identified 27 loci mapping to 72 genes, including genes with reported links to circadian regulation or circadian-related pathways, such as CALCA, DHCR7, KDM5A, HAL, and CRX. Five genes (EPHB1, SERPING1, C12orf74, PLEKHG7, and EEA1) were observed in the CII analysis but not in component-specific analyses. LOCO analyses indicated that the CII genetic signal was not reducible to any single component. The CII PRS was associated with metabolic and psychiatric phenotypes. CII was genetically correlated with insomnia, mood swings, body mass index, type 2 diabetes, coronary artery disease, and myocardial infarction. MR analyses provided suggestive directional evidence, strongest for reverse associations of mood swings and coronary artery disease with CII. Interpretation The CII captures a polygenic composite susceptibility signal associated with cardiometabolic and mood outcomes, with suggestive evidence of directional relationships. Funding European Research Council Advanced Grant CLOCKrisk (101053225).

Ambient PM2.5 exposure and sleep quality: Evidence from circadian DNA methylation signatures in a population-based study.

Sleep disturbance is prevalent in aging populations, yet its association with ambient PM2.5 remains insufficiently characterized due to the lack of reliable molecular biomarkers. We leveraged 2350 middle-aged and older adults from the Guangxi Eco-Environmental Health and Aging Study to examine the association between PM2.5 exposure and sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI) and to identify relevant DNA methylation signatures of circadian rhythm genes. Higher PM2.5 was significantly associated with worse sleep outcomes, with the strongest associations for the 2-month exposure window. Particularly, per 10 μg/m3 increase in the 2-month average PM2.5 was associated with a 1.33-point increase in PSQI score (95% CI: 0.95, 1.71), a 0.79-hour reduction in sleep duration (95% CI: -0.99, -0.59), and higher odds of poor sleep quality (odds ratio [OR] =2.17, 95% CI: 1.69, 2.80) and abnormal sleep duration (OR =1.59, 95% CI: 1.24, 2.03). A two-stage analysis of DNA methylation signatures identified 47 sleep-related CpG sites, of which 11 were selected using LASSO penalization to construct the sleep-quality-related methylation risk score (MRS). Mediation analyses further identified five CpGs annotated to NPAS2, PRKAG2, RORA, and CSNK2A2 that partially mediated the association between PM2.5 exposure and sleep quality (mediation proportions: 9.08%-15.98%), whereas the sleep MRS accounted for a higher mediation proportion than individual CpGs (25.03%). Our findings underscore ambient PM2.5 exposure as a relevant environmental factor linked to impaired sleep quality and highlight that circadian epigenetic signatures could serve as molecular markers of vulnerability to pollution-related sleep disturbances.

CLOCK 3111T/C Polymorphism and Sex Moderate the Effect of Childhood Trauma on White Matter Microstructure in Bipolar Disorder

Background. Bipolar disorder (BD) is characterized by circadian rhythm disruptions, contributing to mood instability and recurrence. These rhythms are regulated by clock genes in the suprachiasmatic nucleus, including the CLOCK 3111T/C (rs1801260) polymorphism that has been linked to delayed sleep phase, insomnia, and altered circadian expression. Both circadian disruption and adverse childhood experiences (ACEs) correlate with white matter (WM) abnormalities. We hypothesized that rs1801260 moderates ACE effects on WM microstructure in BD. Methods. We enrolled 137 BD patients in depressive episodes. Participants underwent 3T MRI, rs1801260 genotyping and completed the Childhood Trauma Questionnaire. Moderation (PROCESS) tested genotype–ACE interactions on whole-brain fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) values; voxel-wise TBSS (FSL Randomize) localized effects, with sex-stratified and GLZ analyses for genotype–sex interactions. Results. Significant rs1801260 × ACE interactions emerged for FA and RD across physical abuse, physical neglect, and emotional neglect. Higher ACEs were associated with lower FA/higher RD only in CLOCK rs1801260*C carriers, mainly females. TBSS showed physical abuse × rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse × sex × rs1801260 interactions on FA/RD, with effects specific to female CLOCK rs1801260*C carriers but genotype-independent in males. Conclusions. rs1801260 moderates the impact of early-life stress on WM integrity in BD, particularly in emotion-regulation tracts, with CLOCK rs1801260*C carriers showing greater vulnerability. Effects are genotype-specific in females but genotype-independent in males, possibly reflecting sex-dimorphic neurodevelopment driven by estrogen–androgen modulation of clock genes, HPA axis, and myelination.