Eur J Hum Genet. 2016 May 4.

Najaf Amin, Karla V Allebrandt, Ashley van der Spek, Bertram Müller-Myhsok, Karin Hek, Maris Teder-Laving, Caroline Hayward, Tõnu Esko, Josine G van Mill, Hamdi Mbarek, Nathaniel F Watson, Scott A Melville, Fabiola M Del Greco, Enda M Byrne, Edwin Oole, Ivana Kolcic, Ting-hsu Chen, Daniel S Evans, Josef Coresh, Nicole Vogelzangs, Juha Karjalainen, Gonneke Willemsen, Sina A Gharib, Lina Zgaga, Evelin Mihailov, Katie L Stone, Harry Campbell, Rutger WW Brouwer, Ayse Demirkan, Aaron Isaacs, Zoran Dogas, Kristin D Marciante, Susan Campbell, Fran Borovecki, Annemarie I Luik, Man Li, Jouke Jan Hottenga, Jennifer E Huffman, Mirjam CGN van den Hout, Steven R Cummings, Yurii S Aulchenko, Philip R Gehrman, André G Uitterlinden, Heinz-Erich Wichmann, Martina Müller-Nurasyid, Rudolf SN Fehrmann, Grant W Montgomery, Albert Hofman, Wen Hong Linda Kao, Ben A Oostra, Alan F Wright, Jacqueline M Vink, James F Wilson, Peter P Pramstaller, Andrew A Hicks, Ozren Polasek, Naresh M Punjabi, Susan Redline, Bruce M Psaty, Andrew C Heath, Martha Merrow, Gregory J Tranah, Daniel J Gottlieb, Dorret I Boomsma, Nicholas G Martin, Igor Rudan, Henning Tiemeier, Wilfred FJ van IJcken, Brenda W Penninx, Andres Metspalu, Thomas Meitinger, Lude Franke, Till Roenneberg and Cornelia M van Duijn.

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 30377 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-valueso2.9×10−11) 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.