rs57875989

badMag 3.8

This is a coding sequence variant variant in the PER3 gene.

Key Literature Trait Associations

Delayed Sleep-Wake Phase Disorder

The PER3 VNTR 4-repeat allele (PER3-4) is significantly enriched in patients with delayed sleep-wake phase disorder (DSWPD): 75% of DSWPD patients were homozygous 4/4. The shorter repeat attenuates PER3 protein abundance, weakening the homeostatic sleep pressure signal and shifting the sleep-wake cycle toward eveningness. PER3-4 carriers show reduced slow-wave activity rebound after sleep deprivation and perform worse on sustained attention tasks under sleep loss.

Archer SN et al. “A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference.” Sleep 26(4):413-415 (2003)

Allele G

OR —

p 4.0e-2

Candidate gene study

Magee M et al. “A PERIOD3 variable number tandem repeat polymorphism modulates melatonin treatment response in delayed sleep-wake phase disorder.” Journal of Pineal Research (2020)

Allele G

OR —

p 8.0e-3

N 104

Candidate gene study

multi-ancestry

Archer SN et al. “Phenotyping of PER3 variants reveals widespread effects on circadian preference, sleep regulation, and health.” Sleep Medicine Reviews (2018)

Allele G

OR —

p —

Candidate gene study

multi-ancestry

Sleep Deprivation Vulnerability

PER3 4/4 individuals show substantially greater cognitive performance deterioration during sustained wakefulness compared with PER3 5/5 individuals. Under 40-hour sleep deprivation, 4/4 carriers exhibit greater deficits in psychomotor vigilance and working memory, particularly during the circadian trough (02:00-08:00 h), reflecting impaired homeostatic sleep drive.

Viola AU et al. “PER3 polymorphism predicts sleep structure and waking performance.” Current Biology : Cb (2007)

Allele G

OR —

p —

N 24

Candidate gene study

European

Archer SN et al. “A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference.” Sleep 26(4):413-415 (2003)

Allele G

OR —

p 1.0e-3

Candidate gene study

Goel N et al. “PER3 polymorphism predicts cumulative sleep homeostatic but not neurobehavioral changes to chronic partial sleep deprivation.” Plos One (2009)

Allele G

OR —

p —

N 129

Candidate gene study

European

Hasan S et al. “A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.” Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology (2014)

Allele G

OR —

p —

Candidate gene study

mouse model

Fibromyalgia

A case-control study by Parvez et al. (2024, n=200) found that the PER3(4/4) genotype was significantly associated with fibromyalgia syndrome risk (OR=2.85; 95% CI 1.35–6.0; p=0.008). Allele frequencies differed significantly between fibromyalgia patients and healthy controls. The association is biologically plausible given disrupted circadian rhythmicity and sleep disturbance in fibromyalgia, but this finding requires replication in larger independent cohorts before clinical significance can be assessed.

Parvez S et al. “Unveiling the Role of Human PER3 Gene Polymorphism (rs57875989) as a Potential Risk Factor in Fibromyalgia Syndrome Patients.” Cureus (2024)

Allele 4-REPEAT

OR 2.85

p 8.0e-3

N 200

Candidate gene study

multi-ancestry

Bipolar disorder

Two Turkish case-control studies have examined PER3 rs57875989 in bipolar disorder patients. Aytac et al. (2022, n=195) found that genotype distributions significantly differed between bipolar patients with and without seasonal pattern, and between patients with family history versus controls, implicating the VNTR in circadian-linked BD subtypes. Yegin et al. (2021, n not specified) found the 5/5 genotype associated with protection against BD and linked to hypomanic features. Findings are preliminary and await replication in larger, multi-ethnic cohorts.

Aytac HM et al. “PERIOD3 (PER3) VNTR Variant Associated with Seasonal Pattern and Family History in Bipolar Disorder.” Psychiatria Danubina (2022)

Allele 4-REPEAT

OR —

p —

N 195

Candidate gene study

Turkish

Yegin Z et al. “For whom the circadian clock ticks? Investigation of PERIOD and CLOCK gene variants in bipolar disorder.” Chronobiology International (2021)

Allele 4-REPEAT

OR —

p —

Candidate gene study

Turkish

Depression and anxiety symptoms

In a cross-sectional study of 804 Brazilian young adults, Silva et al. (2020) found that women carrying the PER3(4/4) genotype showed sex-specific effects on anxiety symptomatology and altered interpersonal affect in depression. Evening chronotype — which the 4-repeat allele predisposes to — correlated independently with somatic depressive symptoms, sleep onset delay, and shifted sleep midpoint. The PER3 VNTR polymorphism did not independently predict depression scores in the full sample, and the sex-specific anxiety findings require replication. Liberman et al. (2018, PMID 29614896) also reported that PER3 length polymorphism significantly associated with depressive symptom severity.

Silva ACPE et al. “Depression and anxiety symptoms correlate with diurnal preference, sleep habits, and Per3 VNTR polymorphism (rs57875989) in a non-clinical sample.” Journal of Affective Disorders (2020)

Allele 4-REPEAT

OR —

p —

N 804

Preliminary work

Brazilian

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

Allele 4-REPEAT

OR —

p —

Candidate gene study

multi-ancestry

Gene information from NCBI Gene. Variant classifications from ClinVar.

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