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Genetic variants in RBFOX3 are associated with sleep latency

Research output: Contribution to journalArticle

  • Najaf Amin
  • Karla V Allebrandt
  • Ashley van der Spek
  • Bertram Müller-Myhsok
  • Karin Hek
  • Maris Teder-Laving
  • 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
  • Evelin Mihailov
  • Katie L Stone
  • Rutger Ww Brouwer
  • Ayse Demirkan
  • Aaron Isaacs
  • Zoran Dogas
  • Kristin D Marciante
  • Fran Borovecki
  • Annemarie I Luik
  • Man Li
  • Jouke Jan Hottenga
  • Jennifer E Huffman
  • Mirjam Cgn van den Hout
  • Steven R Cummings
  • 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
  • Jacqueline M Vink
  • 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
  • Henning Tiemeier
  • Wilfred Fj van IJcken
  • Brenda W Penninx
  • Andres Metspalu
  • Thomas Meitinger
  • Lude Franke
  • Till Roenneberg
  • Cornelia M van Duijn

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Original languageEnglish
JournalEuropean Journal of Human Genetics
DOIs
Publication statusPublished - 4 May 2016

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.European Journal of Human Genetics advance online publication, 4 May 2016; doi:10.1038/ejhg.2016.31.

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