2026 ECNP Congress

PS01-1206

CLOCK and PER3 gene interactions and heterozygote advantage influence eating behaviour in bipolar disorder

Burcu Yatkin Guney — I.B. Çakmak, Y. Ulger, E. Goka · Ankara Bilkent City Hospital, Psychiatry, Ankara, Türkiye

2026 ECNP Congress

Background

Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent manic and depressive episodes that impair functioning and quality of life. Beyond genetic vulnerability, disruptions in circadian rhythm regulation are considered a key component of its pathophysiology [1]. These disturbances extend beyond the sleep–wake cycle; to broader biological rhythms, including eating behavior, metabolic processes and sexual functioning [2,3]. Polymorphisms in core clock genes, such as CLOCKand PER3, have been associated with chronotype, sleep quality, and daily behavioral patterns [4]. However, studies examining the combined effects of these gene variants on biological rhythm patterns, eating behavior, and sexual functioning in patients with BD remain limited.

Aims

This study aimed to investigate the effects of CLOCK 3111 T/C (rs1801260) and PER3 VNTR (rs57875989) polymorphisms on circadian rhythm patterns, eating behavior, and sexual functioning in BD within a comprehensive framework.

Methods

The study included 103 BD patients and 86 healthy controls. Data were collected using the sociodemographic data form, the Hamilton Depression Rating Scale, the Young Mania Rating Scale, and the Personal and Social Performance Scale. Sleep quality was assessed using the Pittsburgh Sleep Quality Index; biological rhythms were evaluated with the Biological Rhythms Interview of Assessment in Neuropsychiatry; and circadian rhythm preference was assessed using the Morningness–Eveningness Questionnaire. Eating behavior was measured using the Three-Factor Eating Questionnaire–R21, Eating Attitudes Test–26, Eating Disorder Examination Questionnaire, Emotional Eating Scale and Night Eating Questionnaire, while sexual functioning was assessed using the Arizona Sexual Experiences Scale (ASEX). Genetic analyses were performed on DNA samples obtained from peripheral blood to determine CLOCK and PER3genotypes, using polymerase chain reaction (PCR) and gel electrophoresis methods.

Results

Heterozygosity in circadian genes was associated with more favourable behavioral profiles. CLOCK rs1801260 AG carriers showed more regular eating rhythms and lower night eating scores compared to homozygotes (p=0.032; p=0.016). Similarly, PER3 VNTR 4/5 carriers exhibited lower uncontrolled eating (p=0.012), emotional eating (p < 0.001), overall eating pathology (p = 0.017), and disturbed eating attitudes (p=0.035)than homozygotes. Gene–gene interaction analyses revealed a significant CLOCK×PER3 effect on emotional eating (p=0.023), with higher scores observed in individuals homozygous for both genes, while this effect was attenuated in CLOCK heterozygotes. A significant Group×CLOCK×PER3interaction was also found for total eating behavior scores (p=0.022). Additionally, the CLOCK×PER3 interaction was associated with sexual functioning (p=0.013), with higher ASEX scores observed in BD patients carrying the CLOCK AG and PER3 homozygous combination (p=0.027).

Conclusions

These findings suggest that circadian genetic variation plays a significant role in shaping behavioural variability in BD. Heterozygosity in CLOCK (rs1801260) and PER3 VNTR polymorphisms appears to be associated with more adaptive biological rhythm and eating behaviour profiles, while gene–gene interactions may influence emotional eating and sexual functioning. To our knowledge, this is among the first studies to demonstrate a heterozygote advantage (overdominant model) linking circadian gene variants with biological rhythms and eating behaviour in BD. However, given the cross-sectional design, causal inferences remain limited. Future research should prioritize the integration of genetic profiling into clinical practice.

References

  1. Alloy LB, Ng TH, Titone MK, Boland EM. Circadian Rhythm Dysregulation in Bipolar Spectrum Disorders. Curr Psychiatry Rep. 2017 Apr 1;19(4):21.
  2. Huang W, Ramsey KM, Marcheva B, Bass J. Circadian rhythms, sleep, and metabolism. J Clin Invest. 2011 Jun 1;121(6):2133.
  3. Sciarra F, Franceschini E, Campolo F, Gianfrilli D, Pallotti F, Paoli D, et al. Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Infertility. International Journal of Molecular Sciences 2020, Vol 21, Page 3943. 2020 May 30;21(11):3943.
  4. Chung J, Kim YC, Jeong JH. Bipolar Disorder, Circadian Rhythm and Clock Genes. Clinical Psychopharmacology and Neuroscience. 2023;22(2):211.