rs228697

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This is a protein-altering variant in the PER3 gene.

Key Literature Trait Associations

Chronotype (Morning/Evening Preference)

The PER3 gene is a core component of the circadian clock. The rs228697 G allele causes a Pro864Ala substitution that disrupts an SH3-binding domain, stabilizing PER3 protein and altering recruitment of PER2 into the CLOCK/BMAL1 repressor complex. In a systematic screening of 29 clock gene polymorphisms, this variant was significantly more common in evening chronotypes (OR 2.48, Bonferroni-corrected p = 0.012). Note: this SNP is in PER3, not PER2 as sometimes misreported.

Hida A et al. “Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder.” Scientific Reports 4(1):6309 (2014)

Allele G

OR 2.48

p 1.2e-2

Candidate gene study

Turco M et al. “Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3.” Scientific Reports (2017)

Allele G

OR 2.10

p 1.0e-2

N 786

Preliminary work

European

Anderson A et al. “Circadian Effects on Performance and Effort in Collegiate Swimmers.” Journal of Circadian Rhythms (2018)

Allele G

OR —

p —

N 27

Candidate gene study

European

Anxiety

Homozygosity for the G allele at rs228697 has been associated with significantly elevated self-reported anxiety in a study of 546 undergraduates. However, large-scale machine-learning analysis of 90,882 UK Biobank participants found that the heterozygous CG genotype at rs228697, when co-occurring with specific ZBTB20 genotypes, conferred a near 40-fold reduction in odds of severe anxiety. These divergent findings suggest the rs228697 effect on anxiety is highly dependent on genetic background and cannot be interpreted in isolation. Evidence is consistent with a circadian-mediated mood pathway, with evening chronotype partially mediating the anxiety association in females.

Ventresca C et al. “Machine learning analyses reveal circadian clock features predictive of anxiety among UK biobank participants.” Scientific Reports (2023)

Allele G

OR —

p —

N 90,882

Major Consortium Study

European

Liberman AR et al. “Modeling Strengthens Molecular Link between Circadian Polymorphisms and Major Mood Disorders.” Journal of Biological Rhythms (2018)

Allele G

OR —

p —

N 546

Preliminary work

European

Antidepressant adverse effects

In a cohort of 600 Chinese patients with major depressive disorder treated with SSRIs, individuals homozygous for the C allele at rs228697 (CC genotype) demonstrated significantly higher sleep disturbance scores compared to CG carriers (F=4.027, p=0.046). This suggests that the common C allele may predispose to sleep-related SSRI side effects, though the association is based on a single candidate-gene study and requires replication. The mechanism may involve altered PER3-mediated circadian regulation of serotonin signaling pathways.

Xu Y et al. “Association Between Period 3 Gene Polymorphisms and Adverse Effects of Antidepressants for Major Depressive Disorder.” Genetic Testing and Molecular Biomarkers (2019)

Allele C

OR —

p 4.6e-2

N 600

Preliminary work

East Asian

Gene information from NCBI Gene. Variant classifications from ClinVar.

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