Genetic variants in RBFOX3 are associated with sleep latency

Najaf Amin, Karla V. Allebrandt, Ashley van der Spek, Bertram Mueller-Myhsok, Karin Hek, Maris Teder-Laving, Caroline Hayward, Tonu 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 VogelzangsJuha 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 C. G. N. van den Hout, Steven R. Cummings, Yuru S. Aulchenko, Philip R. Gehrman, Andre G. Uitterlinden, Heinz-Erich Wichmann, Martina Muller-Nurasyid, Rudolf S. N. 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 F. J. van IJcken, Brenda W. Penninx, Andres Metspalu, Thomas Meitinger, Lude Franke, Till Roenneberg, Cornelia M. van Duijn, B. Müller-Myhsok, M.F. Del Greco, W. Hong

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26 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1488-1495
JournalEuropean journal of human genetics
Issue number10
Publication statusPublished - Oct 2016

Cohort Studies

  • Netherlands Twin Register (NTR)

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