Multi-SNP Haplotypes in Circadian PER3 Gene Are Associated with Mood and Sleep Disorders in University Students

<b>Background</b>: Mood disorders, including anxiety, depression, and seasonal affective disorder (SAD), are often comorbid and can be exacerbated by the misalignment of an individual's circadian rhythm with their social timing. Single-nucleotide polymorphisms (SNPs) in circadian clock genes have been associated with both internalizing disorders and sleep disturbances, and some clock polymorphisms, including those in the <i>Period3 (PER3)</i> gene, likely function via delaying or advancing circadian period and affecting sleep-wake patterns. <b>Methods</b>: Here, we explore associations of multiple SNP haplotypes in the <i>PER3</i> gene with anxiety, depression, internalizing disorder (ID), chronotype, and sleep disturbance in young adults (<i>n</i> = 1109 individuals). <b>Results</b>: We report novel, sex-specific associations of single <i>PER3</i> SNPs with mood and sleep disorders and highlight strong multi-SNP haplotype associations, revealing a greater risk of mood and sleep disorders in university students with specific <i>PER3</i> haplotypes. <b>Conclusions</b>: Our results suggest that the additive effects of multiple risk variants amplify the prevalence of mood disorders and sleep disruptions in young adults. Understanding how polymorphisms within circadian genes interact to alter clock function, sleep-wake behavior and downstream physiological changes in the brain may help explain the comorbidity of mood and sleep syndromes and provide future therapeutic targets to combat these debilitating disorders.