8288098 Uncovering the genetic basis of circadian disruption risk: genome-wide association study of a circadian imbalance index

<h3>Objective</h3> Circadian rhythms regulate key physiological functions and are influenced by environmental, behavioral, and genetic factors. We conducted a genome-wide association study (GWAS) of the Circadian Imbalance Index (CII)—a composite phenotype incorporating eveningness, abnormal sleep duration, high neuroticism, atypical caffeine intake, and low vitamin D levels—to identify genetic variants associated with circadian disruption, particularly relevant for night shift workers. <h3>Material and Methods</h3> We analyzed 308,211 UK Biobank participants of European ancestry. The CII (range 0–5) was derived from self-reported and biomarker data. GWAS was adjusted for age, sex, assessment center, genotyping batch, and 20 principal components of ancestry. Variants with MAF &lt;1% and imputation quality R² &lt;0.7 were excluded. Functional annotation and enrichment analyses were conducted using FUMA and MAGMA. <h3>Results</h3> GWAS identified 190 genome-wide significant SNPs (p&lt;5×10^-⁸), mapping to 57 lead variants in 27 genomic loci. Seventy-two mapped genes were associated with circadian regulation and pleiotropic traits spanning psychiatric, metabolic, and cardiovascular domains. Enriched expression was found in brain regions including the cerebellum, frontal cortex, and nucleus accumbens. Gene set enrichment implicated vitamin D metabolism and the Nikolsky breast cancer amplicon gene set. <h3>Conclusion</h3> The CII is a heritable, polygenic trait reflecting shared genetic risk for circadian disruption and related health conditions. Identified pathways, particularly those involving vitamin D metabolism and neuropsychiatric regulation, offer insights into the biological underpinnings of circadian misalignment. These findings are especially relevant to night shift workers, who are at elevated risk of circadian-related health issues. Understanding genetic susceptibility can inform interventions to mitigate risks in this population.