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Eur J Hum Genet. 2016 Oct;24(10):1488-95. doi: 10.1038/ejhg.2016.31. Epub 2016 May 4.

Genetic variants in RBFOX3 are associated with sleep latency.

Author information

1
Unit of Genetic Epidemiology, Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
2
Institute of Medical Psychology, Ludwig-Maximilians-University, Munich, Germany.
3
Max-Planck-Institute of Psychiatry, Munich, Germany.
4
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
5
Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
6
Estonian Genome Center, University of Tartu and Estonian Biocenter, Tartu, Estonia.
7
Medical Research Council, Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, Scotland.
8
Department of Psychiatry, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
9
Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
10
Department of Neurology, University of Washington, Seattle, WA, USA.
11
University of Washington Medicine Sleep Center, Seattle, WA, USA.
12
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
13
Center for Biomedicine, European Academy of Bolzano, Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany.
14
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
15
Queensland Institute of Medical Research, Brisbane, QLD, Australia.
16
Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
17
School of Medicine, University of Split, Split, Croatia.
18
VA Boston Healthcare System, Boston University, Boston, MA, USA.
19
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
20
Departments of Epidemiology, Biostatistics, and Medicine, Johns Hopkins University, Baltimore, MD, USA.
21
Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
22
Department of Medicine, Division of Pulmonary & Critical Care Medicine, University of Washington, Seattle, WA, USA.
23
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
24
Department of Neuroscience and Sleep Medicine Centre, University of Split School of Medicine, Split, Croatia.
25
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
26
Centre for Functional Genomics and Department of Neurology, Faculty of Medicine, University of Zagreb, Zagreb, Croatia.
27
Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
28
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
29
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
30
Netherlands Consortium for Healthy Ageing and National Genomics Initiative, Leiden, The Netherlands.
31
Institute of Epidemiology I, Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg, Germany.
32
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University and Klinikum Grosshadern, Munich, Germany.
33
Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.
34
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
35
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
36
DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
37
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
38
Department of Neurology, General Central Hospital, Bolzano, Italy.
39
Department of Neurology, University of Lübeck, Lübeck, Germany.
40
Centre for Global Health, University of Split School of Medicine, Split, Croatia.
41
Department of Pulmonary Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
42
Department of Medicine, Brigham and Women's Hospital and Beth Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
43
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
44
Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
45
Department of Psychiatry, Washington University, St Louis, MO, USA.
46
VA Boston Healthcare System, Boston, MA, USA.
47
Department of Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
48
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
49
Institute of Human Genetics, Techinsche Universität München, München, Germany.
50
Centre for Medical Systems Biology, Leiden, The Netherlands.

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.

PMID:
27142678
PMCID:
PMC5027680
DOI:
10.1038/ejhg.2016.31
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Dr Najaf Amin is supported by the Netherlands Brain Foundation (project number F2013(1)-28). Dr Gregory J Tranah was supported by NIA grant R01AG030474. Dr Henning Tiemeier was supported by the Vidi Grant of ZonMw (the Netherlands Organization for Health Research and Development, 2009-017.106.370). All other authors report no biomedical financial interests or potential conflicts of interest.

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