A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans

Abstract

The three PERIOD proteins form a major negative feedback component of the molecular mechanism governing the periodicity of the vertebrate circadian clock. Genetic variations within the human PER2 and PER3 genes have been linked with diurnal preference and disorders of sleep timing. We screened the coding region of PER1, as well as the 5¢-and 3¢-untranslated regions and the promoter region, for polymorphisms. The T2434C polymorphism in exon 18, a synonymous substitution, associated with extreme diurnal preference. The C allele was more frequent in subjects with extreme morning preference (frequency = 0.24) than in subjects with extreme evening preference (frequency = 0.12). No significant association was observed between either allele and delayed sleep phase syndrome. This polymorphism may have a direct effect on RNA translatability, or be in linkage disequilibrium with another polymorphism which affects PER1 expression at the DNA, RNA, or protein level. This is the first reported association between a PER1 polymorphism and extreme diurnal preference. Functionally important polymorphisms in PER1 are rare, which may indicate that it is subject to more stringent selection pressure than the other PER genes.

Variants in circadian genes and prostate cancer risk: a population-based study in China

“…32 In men with normal sleep patterns and those with obstructive sleep apnea, sleep fragmentation resulted in significant reductions in nocturnal testosterone; 33,34 similar disruptions in testosterone rhythm are also seen in prostate cancer patients. 35 Since variants in PER genes are associated with delayed sleep phase syndrome and extreme diurnal preference, 22,23,36,37 it is plausible that variants in PER genes are associated with different serum steroid hormone levels thus affecting risk for hormone-related cancers. Interestingly, the PER3 structural variant that was associated with an increased prostate cancer risk in a subgroup of men in this study was also linked to an increased risk for breast cancer among premenopausal women.…”

Circadian genes, rhythms and the biology of mood disorders

“…Even individuals that are genetically predisposed towards "eveningness" (a preference for the evening) versus "morningness" (a preference for the morning) are more likely to develop depression (Drennan et al, 1991;Chelminski et al, 1999). Genetic variations in the circadian genes have been found to associate with these sleep disorders and diurnal preference measures including an association between certain variants of Per2, and CK1δ with FASPS; Per3, CLOCK, and CK1ε with DSPS; and Per1, Per2, Per3 and CLOCK with diurnal preference (Katzenberg et al, 1998;Iwase et al, 2002;Archer et al, 2003;Johansson et al, 2003;Takano et al, 2004;Carpen et al, 2005;Mishima et al, 2005;Xu et al, 2005;Carpen et al, 2006;Vanselow et al, 2006). This suggests a connection between proper mood regulation and a normal functioning circadian clock.…”

Genotype-Dependent Differences in Sleep, Vigilance, and Response to Stimulants

“…Screening for missense mutations or functional polymorphisms in promoter and 5'-and 3'-UTRs of the human PER1 gene in volunteers with extreme diurnal preference and patients with delayed sleep phase syndrome (DSPS) remained unsuccessful [106]. Moreover, a synonymous A to G substitution at nucleotide 2548 showed no association with eveningnessmorningness tendencies [107].…”