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

TL;DR

This study links a Circadian Imbalance Index to genes related to diabetes, mood, and heart disease in over 300,000 UK Biobank participants.

Contribution

A novel Circadian Imbalance Index was developed and genetically linked to metabolic, cardiovascular, and mood traits.

Findings

27 loci and 72 genes were identified, including circadian regulators like CALCA and DHCR7.

A polygenic score for CII was associated with type 2 diabetes, depression, and obesity.

Genetic correlations and Mendelian randomization suggest causal links between CII and health outcomes.

Abstract

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.

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