Genetic architecture of a Circadian Imbalance Index: genome-wide association, phenome-wide association, and Mendelian randomisation analyses
Year: 2026
Type: article
Study design: Observational Study
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. 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. 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. INTERPRETATION: The CII captures a polygenic composite susceptibility signal associated with cardiometabolic and mood outcomes, with suggestive evidence of directional relationships. FUNDING: European Research Council Advanced Grant CLOCKrisk (101053225).
Source: EBioMedicine
Institutions: Broad Institute, Medical University of Vienna, Norwegian University of Science and Technology, Central Queensland University, Brigham and Women's Hospital, Harvard University, Massachusetts General Hospital, Monash University, University of Bristol, University of Oxford, MRC Integrative Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, NIHR Manchester Biomedical Research Centre
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,780
Funders: Massachusetts General Hospital, Cancer Research UK, European Commission, Universität Wien, Medizinische Universität Wien, National Institutes of Health, NIHR Oxford Biomedical Research Centre, Cancer Research UK Cancer Imaging Centre, National Heart, Lung, and Blood Institute, National Cancer Institute, H2020 European Research Council, HORIZON EUROPE European Research Council
Awards: G1131969086, G323433674, G324601231, G360954899, Targeting the circadian clock in personalized disease prevention, Premenopausal Hormone Levels and Risk of Breast Cancer, Integrating lifecourse approaches, biologic and digital phenotypes in support of heart and lung disease epidemiologic research, Life Course Cancer Epidemiology Cohort in Women
OpenAlex ID: W7169843630