Abstract
Individual circadian clocks entrain differently to environmental cycles (zeitgebers, e.g., light and darkness), earlier or later within the day, leading to different chronotypes. In human populations, the distribution of chronotypes forms a bell-shaped curve, with the extreme early and late types _ larks and owls, respectively _ at its ends. Human chronotype, which can be assessed by the timing of an individual's sleep-wake cycle, is partly influenced by genetic factors - known from animal experimentation. Here, we review population genetic studies which have used a questionnaire probing individual daily timing preference for associations with polymorphisms in clock genes. We discuss their inherent limitations and suggest an alternative approach combining a short questionnaire (Munich ChronoType Questionnaire, MCTQ), which assesses chronotype in a quantitative manner, with a genome-wide analysis (GWA). The advantages of these methods in comparison to assessing time-of-day preferences and single nucleotide polymorphism genotyping are discussed. In the future, global studies of chronotype using the MCTQ and GWA may also contribute to understanding the influence of seasons, latitude (e.g., different photoperiods), and climate on allele frequencies and chronotype distribution in different populations.
Highlights
When circadian rhythms are investigated under constant conditions, their endogenous periods often deviate from 24 h
Besides finding advanced sleep phase syndrome (ASPS) to be associated in isolated families with single nucleotide mutations, the same phenotype has been associated in the general population with a length polymorphism in the period 3 (Per3) gene, in form of variable number of tandem repeats (VNTR; Table 1) [15,16]
Genome-wide studies of the genetic variability underlying chronotype and the circadian system in general will help us to identify those genes that are relevant for circadian regulation in humans and how the circadian system has evolved
Summary
When circadian rhythms are investigated under constant conditions, their endogenous periods often deviate from 24 h. To characterize the relevance of mammalian clock genes in humans, association studies of a circadian phenotype with naturally occurring genetic variation have been conducted These efforts are based primarily on a phenotyping instrument that queries time-of-day preferences, resulting in a score We review these studies and discuss inherent problems possibly responsible for inconsistencies of some results. Besides finding ASPS to be associated in isolated families with (rare) single nucleotide mutations, the same phenotype has been associated in the general population with a length polymorphism in the period 3 (Per3) gene, in form of variable number of tandem repeats (VNTR; Table 1) [15,16]. One of them responsible for the phenotype and the other
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