Genetic variants in RBFOX3 are associated with sleep latency

N. Amin, K.V. Allebrandt, A. Spek, B. Müller-Myhsok, K. Hek, M. Teder-Laving, C. Hayward, T. Esko, J.G. van Mill, H. Mbarek, N.F. Watson, S.A. Melville, M.F. Del Greco, E.M. Byrne, E. Oole, I. Kolcic, T. Chen, D.S. Evans, J. Coresh, N. VogelzangsJ. Karjalainen, G. Willemsen, S.A. Gharib, L. Zgaga, E. Mihailov, K.L. Stone, H. Campbell, R.W.W. Brouwer, A. Demirkan, A. Isaacs, Z. Dogas, K. Marciante, S. Campbell, F. Borovecki, A.I. Luik, M. Li, J.J. Hottenga, J.E. Huffman, M.C.G.N. van den Hout, S.R. Cummings, Y.S. Aulchenko, P.R. Gehrman, A.G. Uitterlinden, H.E. Wichmann, M. Müller-Nurasyid, R.S.N. Fehrmann, G.W. Montgomery, A. Hofman, W. Hong, L. Kao, B.A. Oostra, A.F. Wright, J.M. Vink, J.F. Wilson, P.P. Pramstaller, A.A. Hicks, O. Polasek, N.M. Punjabi, S. Redline, B.M. Psaty, A.C. Heath, M. Merrow, G.J. Tranah, D.J. Gottlieb, D.I. Boomsma, N.G. Martin, I. Rudan, H. Tiemeier, W.F.J. van Ijcken, B.W.J.H. Penninx, A. Metspalu, T. Meitinger, L. Franke, T. Roenneberg, C.M. van Duijn

Research output: Contribution to JournalArticleAcademicpeer-review

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
JournalEuropean Journal of Human Genetics
Volume24
Issue number10
DOIs
Publication statusPublished - 2016

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    Amin, N., Allebrandt, K. V., Spek, A., Müller-Myhsok, B., Hek, K., Teder-Laving, M., ... 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