In vivo molecular chronotyping, circadian misalignment, and high rates of depression in young adults

•We present molecular evidence linking depression in young adults with in vivo mRNA phase misalignment in circadian molecular clocks.•Using an independent, data-driven cluster analysis, we can define the molecular circadian misalignment of individuals from peripheral clock gene expression.•The risk of being depressed is higher in young adults with delayed phase and in individuals with a mismatch between circadian behavioral phenotypes and circadian molecular phase, independent of sleep duration, social jetlag and gender. Young adults are disproportionately affected by depression and related mental disorders. Circadian misalignment (a phase advance or delay in the body's internal clock timing) is thought to exert adverse effects on downstream physiological processes regulating mood. Circadian disruption may represent an additional, under-appreciated risk factor affecting young adults. Here, we test the hypothesis that depression in young adults is associated with circadian misalignment—the lack of concordance between an individual's endogenous rhythm and their external social and academic environment. We screened 528 individuals for morningness-eveningness diurnal preference and sleep-wake chronotype. We selected individuals with extreme scores (n = 130) for estimation of circadian phase by measuring clock gene mRNA oscillations in hair follicles (a peripheral clock). Using an independent, data-driven cluster analysis, we define the circadian misalignment of both advanced- and delayed-phase individuals from clock gene mRNA expression levels. We compare depression (BDI-II), anxiety (STAI), social jetlag, sleep duration, and sleep disturbance (PROMIS) scores between misaligned individuals and control individuals of intermediate chronotype (n = 173). We demonstrate that depression scores in young adults are significantly higher in individuals with circadian phase delays and in individuals with a mismatch between circadian behavioral phenotypes and circadian molecular phase. Evening-type individuals with circadian phase delays are 20 times more likely and mismatched individuals are 5–8 times more likely to be depressed than control individuals. Sleep disturbance shows a similar relationship with circadian phenotypes, but the mood effects described in this study are independent of sleep duration, social jetlag and gender. Our study examined peripheral clock genes that represents a circadian rhythm potentially influenced by both intrinsic and external, environmen