| Title: | Genetic architecture of a Circadian Imbalance Index: genome-wide association, phenome-wide association, and Mendelian randomisation analyses |
| Journal: | EBioMedicine |
| Published: | 21 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42481375/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2026.106380 |
Publication 21421
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Abstract
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.</p>
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.</p>
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.</p>
INTERPRETATION: The CII captures a polygenic composite susceptibility signal associated with cardiometabolic and mood outcomes, with suggestive evidence of directional relationships.</p>
FUNDING: European Research Council Advanced Grant CLOCKrisk (101053225).</p>
13 Keywords
- Chronotype
- Circadian Rhythm
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Humans
- Male
- Mendelian Randomization Analysis
- Multifactorial Inheritance
- Phenomics
- Phenotype
- Polymorphism, Single Nucleotide
14 Authors
- Magdalena Żebrowska
- Matthias Wielscher
- Jing Zhang
- Ingvild Saksvik-Lehouillier
- Lee DiMilia
- Angus Burns
- Jesse Valliere
- Leonardo Vincenzi
- Susan Redline
- Olivia Okereke
- Richa Saxena
- Rebecca Richmond
- Martin K. Rutter
- Eva S. Schernhammer
1 Application
| Application ID | Title |
|---|---|
| 48576 | A multi-polygenic score of clock resilience and its utility in predicting vulnerability to night work with regards to chronic disease risk (cardiovascular disease, type 2 diabetes, depression, breast) |
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