Genome wide association study of a Circadian Imbalance Index in 312,935 European ancestry UK Biobank participants identifies loci related to diabetes, mood and myocardial infarction

The Circadian Imbalance Index (CII) integrates chronotype, sleep duration, neuroticism, caffeine intake, and vitamin D. In a genome wide association study (GWAS) of CII in 312,935 European ancestry UK Biobank participants, we identified 27 loci mapping to 72 genes, including circadian regulators CALCA, DHCR7, KDM5A, HAL, and CRX. Gene-overlap analyses demonstrated shared architecture with CII components, while EPHB1, SERPING1, C12orf74, PLEKHG7, and EEA1 were uniquely associated with CII. A CII polygenic score (CII-PRS) showed phenome-wide associations with type 2 diabetes (T2D), major depressive disorder, and obesity. Genetic correlations linked CII with insomnia, mood symptoms, body mass index (BMI), T2D, coronary artery disease (CAD), and myocardial infarction (MI). Mendelian randomization suggested causal effects of CII on T2D, mood swings, and MI, and reverse effects of CAD, mood, and MI on CII. This work shows that circadian imbalance is a polygenic trait connecting sleep-related biology to metabolic, cardiovascular and mood health outcomes.