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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.* ; Vogelzangs, N.* ; Karjalainen, J.* ; Willemsen, G.* ; Gharib, S.A.* ; Zgaga, L.* ; Mihailov, E.* ; Stone, K.L.* ; Campbell, H.* ; Brouwer, R.W.* ; Demirkan, A.* ; Isaacs, A.* ; Dogas, Z.* ; Marciante, K.D.* ; Campbell, S.* ; Borovecki, F.* ; Luik, A.I.* ; Li, M.* ; Hottenga, J.J.* ; Huffman, J.E.* ; van den Hout, M.C.* ; Cummings, S.R.* ; Aulchenko, Y.S.* ; Gehrman, P.R.* ; Uitterlinden, A.G.* ; Wichmann, H.-E. ; Müller-Nurasyid, M. ; Fehrmann, R.S.N.* ; Montgomery, G.W.* ; Hofman, A.* ; Kao, W.H.* ; Oostra, B.A.* ; Wright, A.F.* ; Vink, J.M.* ; Wilson, J.F.* ; Pramstaller, P.P.* ; Hicks, A.A.* ; Polasek, O.* ; Punjabi, N.M.* ; Redline, S.* ; Psaty, B.M.* ; Heath, A.C.* ; Merrow, M.* ; Tranah, G.J.* ; Gottlieb, D.J.* ; Boomsma, D.I.* ; Martin, N.G.* ; Rudan, I.* ; Tiemeier, H.* ; van IJcken, W.F.J.* ; Penninx, B.W.* ; Metspalu, A.* ; Meitinger, T. ; Franke, L.* ; Roenneberg, T.* ; van Duijn, C.M.*

Genetic variants in RBFOX3 are associated with sleep latency.

Eur. J. Hum. Genet. 24, 1488-1495 (2016)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Linkage Analysis; Onset Insomnia; Recorded Sleep; Candidate-gene; Self-report; Expression; Family; Determinants; Imputation
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Quellenangaben Volume: 24, Issue: 10, Pages: 1488-1495 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed