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Abstract:
Time to fall asleep (sleep latency) is a major determinant of sleep
quality. Chronic, long sleep latency is a major characteristic of
sleep-onset insomnia and/or delayed sleep phase syndrome. In this study
we aimed to discover common polymorphisms that contribute to the
genetics of sleep latency. We performed a meta-analysis of genome-wide
association studies (GWAS) including 2 572 737 single nucleotide
polymorphisms (SNPs) established in seven European cohorts including
4242 individuals. We found a cluster of three highly correlated variants
(rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1
homolog 3 gene (RBFOX3) associated with sleep latency (P-values = 5.77 x
10(-08), 6.59 x 10(-08) and 9.17 x 10(-08)). These SNPs were replicated
in up to 12 independent populations including 30 377 individuals
(P-values = 1.5 x 10(-02), 7.0 x 10(-03) and 2.5 x 10(-03); combined
meta-analysis P-values = 5.5 x 10(-07), 5.4 x 10(-07) and 1.0 x
10(-07)). A functional prediction of RBFOX3 based on co-expression with
other genes shows that this gene is predominantly expressed in brain
(P-value = 1.4 x 10(-316)) and the central nervous system (P-value = 7.5
x 10(-321)). The predicted function of RBFOX3 based on co-expression
analysis with other genes shows that this gene is significantly involved
in the release cycle of neurotransmitters including gamma-aminobutyric
acid and various monoamines (P-values<2.9x10(-11)) that are crucial in
triggering the onset of sleep. To conclude, in this first large-scale
GWAS of sleep latency we report a novel association of variants in
RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the
involvement of RBFOX3 with sleep latency.
