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Review
. 2017 Feb 1;40(2):zsw048.
doi: 10.1093/sleep/zsw048.

Genetic Basis of Chronotype in Humans: Insights From Three Landmark GWAS

David A Kalmbach  1 , Logan D Schneider  2 , Joseph Cheung  2 , Sarah J Bertrand  3 , Thiruchelvam Kariharan  4 , Allan I Pack  5 , Philip R Gehrman  5
Affiliations
Review

Genetic Basis of Chronotype in Humans: Insights From Three Landmark GWAS

David A Kalmbach et al. Sleep. .

Abstract

Study objectives: Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related illnesses. Family studies indicate that chronotype is a heritable trait, thus directing attention toward its genetic basis. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWAS), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. This review discusses the findings of these landmark GWASs in the context of prior research.

Methods: We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype.

Results: A good deal of consistency was observed across studies with 9 genes identified in 2 of the 3 GWASs. Several genes previously unknown to influence chronotype were identified.

Conclusions: GWAS is an important tool in identifying common variants associated with the complex chronotype phenotype, the findings of which can supplement and guide molecular science. Future directions in model systems and discovery of rare variants are discussed.

Keywords: chronotype; circadian rhythms; genetics; genome-wide association study; sleep.

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Figures

Figure 1
Figure 1
Manhattan plot of genome-wide association studies of being a morning person from Hu et al. 2016. Presented in its originally published format, the grey line corresponds to threshold for genome-wide significance at p = 5 × 10–8, with significant results shown above this threshold in red. Gene labels are annotated as the nearby genes to the significant single nucleotide polymorphisms.
Figure 2
Figure 2
Relationship between allele frequency and effect on phenotype expression. Common variants with minor allele frequencies (MAF)>5% typically boast weak or modest effects on expression of complex phenotypes. The effects of common variants are often detected using genome-wide association studies (GWASs). In contrast, rarer variants typically wield stronger effects and contribute to more extreme expressions of complex phenotypes. Rare variants, however, are not often detected using genome-wide analysis.
Figure 3
Figure 3
Comparison of statistical power in the 3 genome-wide association studies (GWASs). Comparisons of the 3 different study designs (number of cases:number of controls) and their power to detect alleles with varying genetic relative risk over the range of effect allele frequencies (EAF). The differences in the power over the range of genotype relative risks clearly indicate the impact of sample size (Jones et al. > Hu et al. > Lane et al.), which figures most prominently at higher allele frequencies. Power estimates were performed using the CaTS power calculator (http://csg.sph.umich.edu//abecasis/cats/) for all studies, using a significance threshold of 5 × 10−8, prevalence of morningness phenotype of 0.652 (estimated from total UK Biobank cohort), and EAF minimum (0.01) and minimum (0.998) values used to reflect the range across studies.
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