Genetic variants in RBFOX3 are associated with sleep latency

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 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 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, Cornelia M van Duijn

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

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 × 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
Number of pages8
JournalEuropean Journal of Human Genetics
Volume24
Issue number10
DOIs
Publication statusPublished - Oct 2016

Keywords

  • GENOME-WIDE ASSOCIATION
  • LINKAGE ANALYSIS
  • ONSET INSOMNIA
  • RECORDED SLEEP
  • CANDIDATE-GENE
  • SELF-REPORT
  • EXPRESSION
  • FAMILY
  • DETERMINANTS
  • IMPUTATION

Cite this

Amin, N., Allebrandt, K. V., van der Spek, A., Müller-Myhsok, B., Hek, K., Teder-Laving, M., Hayward, C., Esko, T., van Mill, J. G., Mbarek, H., Watson, N. F., Melville, S. A., Del Greco, F. M., Byrne, E. M., Oole, E., Kolcic, I., Chen, T-H., Evans, D. S., Coresh, J., ... van Duijn, C. M. (2016). Genetic variants in RBFOX3 are associated with sleep latency. European Journal of Human Genetics, 24(10), 1488-1495. https://doi.org/10.1038/ejhg.2016.31