Machine Learning Analyses Reveal Circadian Clock Features Predictive of Anxiety Among UK Biobank Participants

Abstract

Abstract Mood disorders, including depression and anxiety, affect almost one-fifth of the world’s adult population and are becoming increasingly prevalent. Mutations in circadian clock genes have previously been associated with mood disorders both directly and indirectly through alterations in circadian phase, suggesting that the circadian clock influences multiple molecular pathways involved in mood. By targeting previously identified single nucleotide polymorphisms (SNPs) that have been implicated in anxiety and depressive disorders, we use a combination of statistical and machine learning techniques to investigate associations with anxiety (GAD-7) scores in a UK Biobank sample of 90,882 individuals. As in previous studies, we observed that females exhibited higher GAD-7 scores than males regardless of genotype. Interestingly, we found no significant effects on anxiety from individual circadian gene variants; only circadian genotypes with multiple SNP variants showed significant associations with anxiety. For both sexes, severe anxiety is associated with a 120-fold increase in odds for individuals with CRY2_AG(rs1083852)/ZBTB20_TT(rs1394593) genotypes and is associated with a near forty-fold reduction in odds for individuals with PER3A_CG(rs228697)/ZBTB20_TT(rs1394593) genotypes. We report several sex-specific associations with anxiety. CRY2/ZBTB20 and PER3A/ZBTB20 genotypic combinations were most strongly associated with anxiety in females with the CRY2_AG/ZBTB20_TT genotype associated with a > 200-fold increase in odds of anxiety in females. Mediation analysis revealed direct associations of CRY2/ZBTB20 variant genotypes with moderate anxiety in females and CRY1/PER3A variant genotypes with severe anxiety in males. The association of CRY1/PER3A variant genotypes with severe anxiety in females was partially mediated by extreme evening chronotype. Our results reinforce existing findings that females exhibit stronger anxiety outcomes than males, and provide evidence for circadian gene associations with anxiety, particularly in females. Our findings also implicate ZBTB20 (rs1394593) as a robust factor linking circadian variants to anxiety risk, suggesting that lower expression of this gene significantly modulates the odds of anxiety. Together, these observations provide novel links between the circadian clockwork and anxiety symptoms and identify potential molecular pathways through which clock genes may influence anxiety risk.