Genetic variants in RBFOX3 are associated with sleep latency.
Amin N., Allebrandt KV., van der Spek A., Müller-Myhsok B., Hek K., Teder-Laving M., Hayward C., Esko T., van Mill JG., Mbarek H., Watson NF., Melville SA., Del Greco FM., Byrne EM., Oole E., Kolcic I., Chen T-H., Evans DS., Coresh J., Vogelzangs N., Karjalainen J., Willemsen G., Gharib SA., Zgaga L., Mihailov E., Stone KL., Campbell H., Brouwer RW., Demirkan A., Isaacs A., Dogas Z., Marciante KD., Campbell S., Borovecki F., Luik AI., Li M., Hottenga JJ., Huffman JE., van den Hout MC., Cummings SR., Aulchenko YS., Gehrman PR., Uitterlinden AG., Wichmann H-E., Müller-Nurasyid M., Fehrmann RS., Montgomery GW., Hofman A., Kao WHL., Oostra BA., Wright AF., Vink JM., Wilson JF., Pramstaller PP., Hicks AA., Polasek O., Punjabi NM., Redline S., Psaty BM., Heath AC., Merrow M., Tranah GJ., Gottlieb DJ., Boomsma DI., Martin NG., Rudan I., Tiemeier H., van IJcken WF., Penninx BW., Metspalu A., Meitinger T., Franke L., Roenneberg T., van Duijn CM.
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 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 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 × 10(-316)) and the central nervous system (P-value=7.5 × 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<2.9 × 10(-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.