rs12649507

badMag 2.8

This is a intron variant variant in the CLOCK gene.

Key Literature Trait Associations

Sleep Duration

The CLOCK rs12649507 A allele is associated with shorter habitual sleep duration across two independent European populations (South Tyrol, n=283; Estonia, n=1,011). A allele carriers slept less than G/G homozygotes; the rs12649507/rs11932595 GGAA haplotype was associated with long sleep (>8.5 hours). The variant is located in intron 1 of CLOCK and likely affects transcriptional regulation of the master circadian pacemaker gene, shifting the endogenous period or amplitude of the CLOCK/BMAL1 transcription-translation feedback loop.

Allebrandt KV et al. “CLOCK gene variants associate with sleep duration in two independent populations.” Biological Psychiatry 67(11):1040-1047 (2010)

Allele A

OR —

p 8.7e-3

Candidate gene study

Li Y et al. “Association between the CLOCK gene polymorphism and depressive symptom mediated by sleep quality among non-clinical Chinese Han population.” Journal of Affective Disorders (2022)

Allele A

OR —

p 5.0e-2

N 289

Candidate gene study

Chinese Han

Dashti HS et al. “Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants.” The American Journal of Clinical Nutrition (2015)

Allele A

OR —

p —

Candidate gene study

multi-ancestry

Cluster headache

A Swedish case-control study (449 patients, 677 controls) found a significant association between rs12649507 and cluster headache (p=0.0069), with the association strengthening in patients who reported diurnal rhythmicity of attacks (p=0.0009). Functional experiments in human primary fibroblasts demonstrated that the variant significantly increases CLOCK mRNA expression (p=0.0232), providing a molecular basis for circadian disruption in cluster headache pathophysiology. This is a single-population study and replication in independent cohorts is needed.

Fourier C et al. “A genetic CLOCK variant associated with cluster headache causing increased mRNA levels.” Cephalalgia : an International Journal of Headache (2018)

Allele G

OR —

p 6.9e-3

N 1,126

Preliminary work

Swedish

Insomnia

A Korean longitudinal cohort study (KoGES, n=1,430) found that rs12649507 genotype significantly modified insomnia incidence in a diet-dependent manner: among male carriers, fruit and meat consumption reduced insomnia risk (p=0.006–0.010), while among female carriers, beverage intake substantially increased insomnia risk (p=0.041). The direction of the main SNP effect on insomnia was not uniform across sexes or dietary contexts, suggesting a complex gene-environment interaction rather than a simple risk relationship. Replication in larger, diet-independent cohorts is required.

Lee S et al. “Association between CLOCK Gene Polymorphisms and Insomnia Risk According to Food Groups: A KoGES Longitudinal Study.” Nutrients (2023)

Allele G

OR —

p 6.0e-3

N 1,430

Preliminary work

Korean

Gene information from NCBI Gene. Variant classifications from ClinVar.

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