title: ARNTL (BMAL1) and NPAS2 gene variants contribute to fertility and seasonality.
abstract: BACKGROUND
  Circadian clocks guide the metabolic, cell-division, sleep-wake, circadian and seasonal cycles. Abnormalities in these clocks may be a health hazard. Circadian clock gene polymorphisms have been linked to sleep, mood and metabolic disorders. Our study aimed to examine polymorphisms in four key circadian clock genes in relation to seasonal variation, reproduction and well-being in a sample that was representative of the general population, aged 30 and over, living in Finland.
  
  
  RESULTS
  Single-nucleotide polymorphisms in the ARNTL, ARNTL2, CLOCK and NPAS2 genes were genotyped in 511 individuals. 19 variants were analyzed in relation to 31 phenotypes that were assessed in a health interview and examination study. With respect to reproduction, women with ARNTL rs2278749 TT genotype had more miscarriages and pregnancies, while NPAS2 rs11673746 T carriers had fewer miscarriages. NPAS2 rs2305160 A allele carriers had lower Global Seasonality Scores, a sum score of six items i.e. seasonal variation of sleep length, social activity, mood, weight, appetite and energy level. Furthermore, carriers of A allele at NPAS2 rs6725296 had greater loadings on the metabolic factor (weight and appetite) of the global seasonality score, whereas individuals with ARNTL rs6290035 TT genotype experienced less seasonal variation of energy level.
  
  
  CONCLUSIONS
  ARNTL and NPAS2 gene variants were associated with reproduction and with seasonal variation. Earlier findings have linked ARNTL to infertility in mice, but this is the first time when any polymorphism of these genes is linked to fertility in humans.
authors.affiliation: Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Kovanen
authors.forename: Sirkku T
authors.initials: ST
authors.lastname: Saarikoski
authors.forename: Arpo
authors.initials: A
authors.lastname: Aromaa
authors.forename: Jouko
authors.initials: J
authors.lastname: Lönnqvist
authors.forename: Timo
authors.initials: T
authors.lastname: Partonen
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002940:Circadian Rhythm; D004734:Energy Metabolism; D005260:Female; D005298:Fertility / Q000235:genetics*; D005387:Finland; D005838:Genotype; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012098:Reproduction / Q000235:genetics; D012621:Seasons
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C104264:NPAS2 protein, human