title: Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders.
abstract: BACKGROUND
  The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases,including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian synchronizing signal and vary widely with latitude.
  
  
  RESULTS
  We apply a geographically explicit model to show that out-of-Africa migration, which led humans to occupy a wide latitudinal area, affected the evolutionary history of circadian regulatory genes. The SNPs we identify using this model display consistent signals of natural selection using tests based on population genetic differentiation and haplotype homozygosity. Signals of natural selection driven by annual photoperiod variation are detected for schizophrenia, bipolar disorder, and restless leg syndrome risk variants, in line with the circadian component of these conditions.
  
  
  CONCLUSIONS
  Our results suggest that human populations adapted to life at different latitudes by tuning their circadian clock systems. This process also involves risk variants for neuropsychiatric conditions, suggesting possible genetic modulators for chronotherapies and candidates for interaction analysis with photoperiod-related environmental variables, such as season of birth, country of residence, shift-work or lifestyle habits.
authors.affiliation: Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, LC, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Claudia
authors.initials: C
authors.lastname: Tresoldi
authors.forename: Giorgia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Stefania
authors.initials: S
authors.lastname: Riva
authors.forename: Franca R
authors.initials: FR
authors.lastname: Guerini
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bolognesi
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000220:Adaptation, Biological; D057906:Circadian Clocks / Q000235:genetics*; D019143:Evolution, Molecular; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D005843:Geography; D006239:Haplotypes; D063426:Human Migration; D006801:Humans; D019964:Mood Disorders / Q000235:genetics*; D017440:Photoperiod; D010789:Phototherapy; D020641:Polymorphism, Single Nucleotide