The Circadian Imbalance Index captures a polygenic composite susceptibility signal associated with cardiometabolic and mood outcomes, with suggestive evidence of directional relationships.
Abstract
Summary 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).
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Chronic low-grade inflammation drives cardiometabolic diseases and has a strong genetic basis. Most genome-wide association studies (GWAS) have focused on European populations, limiting knowledge of the genetic influences on inflammation in admixed populations such as those in Brazil.
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, overweight, and the first two principal components of ancestry.
Most participants were male (53%) and not overweight (55%). The median age was 49, and 38% were older adults. In the genome-wide analysis of TNF-α, IL-10, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and adiponectin, 12 SNPs were significantly associated, most of which were intronic. Notably, one signal mapped to the missense variant rs16841009 in the olfactory receptor gene OR6K6. This variant was associated with MCP-1, suggesting a possible involvement in inflammatory responses.
We identified new SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population, including a missense variant in an olfactory receptor gene linked to MCP-1. This association may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
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