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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.    Methodology/Principal Findings  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/Significance    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.

ARNTL (BMAL1) and NPAS2 Gene Variants Contribute to Fertility and Seasonality