title: Genetic Basis of Chronotype in Humans: Insights From Three Landmark GWAS.
abstract: 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.
  
  
  
  We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Departments of Psychiatry and Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: David A
authors.initials: DA
authors.lastname: Kalmbach
authors.affiliation: Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94063.
authors.forename: Logan D
authors.initials: LD
authors.lastname: Schneider
authors.affiliation: Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94063.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital School of Medicine, Baltimore, MD 21205.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bertrand
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Thiruchelvam
authors.initials: T
authors.lastname: Kariharan
authors.affiliation: Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Pack
authors.affiliation: Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Gehrman
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D010641:Phenotype; D012890:Sleep / Q000235:genetics*; D044465:White People / Q000235:genetics
keywords: chronotype; circadian rhythms; genetics; genome-wide association study; sleep