Genetic variants in RBFOX3 are associated with sleep latency

Najaf Amin¹, Karla V Allebrandt², Ashley van der Spek¹, Bertram Müller-Myhsok³, Karin Hek^{4

5}, Maris Teder-Laving⁶, Caroline Hayward⁷, Tõnu Esko⁶, Josine G van Mill⁸, Hamdi Mbarek⁹, Nathaniel F Watson^{10

11}, Scott A Melville¹², Fabiola M Del Greco¹³, Enda M Byrne^{14

15}, Edwin Oole¹⁶, Ivana Kolcic¹⁷, Ting-Hsu Chen¹⁸, Daniel S Evans¹⁹, Josef Coresh²⁰, Nicole Vogelzangs⁸, Juha Karjalainen²¹, Gonneke Willemsen⁹, Sina A Gharib^{11

22}, Lina Zgaga⁷, Evelin Mihailov⁶, Katie L Stone¹⁹, Harry Campbell²³, Rutger Ww Brouwer¹⁶, Ayse Demirkan¹, Aaron Isaacs¹, Zoran Dogas²⁴, Kristin D Marciante²⁵, Susan Campbell⁷, Fran Borovecki²⁶, Annemarie I Luik⁴, Man Li²⁷, Jouke Jan Hottenga⁹, Jennifer E Huffman⁷, Mirjam Cgn van den Hout¹⁶, Steven R Cummings¹⁹, Yurii S Aulchenko¹, Philip R Gehrman²⁸, André G Uitterlinden^{4

29

30}, Heinz-Erich Wichmann^{31

32

33}, Martina Müller-Nurasyid^{31

34

35

36}, Rudolf Sn Fehrmann²¹, Grant W Montgomery¹⁵, Albert Hofman^{4

37}, Wen Hong Linda Kao²⁷, Ben A Oostra¹, Alan F Wright⁷, Jacqueline M Vink⁹, James F Wilson^{7

23}, Peter P Pramstaller^{13

38

39}, Andrew A Hicks¹³, Ozren Polasek^{17

40}, Naresh M Punjabi⁴¹, Susan Redline⁴², Bruce M Psaty^{43

44}, Andrew C Heath⁴⁵, Martha Merrow², Gregory J Tranah¹⁹, Daniel J Gottlieb^{42

46}, Dorret I Boomsma⁹, Nicholas G Martin¹⁵, Igor Rudan²³, Henning Tiemeier^{4

5

47}, Wilfred Fj van IJcken¹⁶, Brenda W Penninx⁸, Andres Metspalu⁶, Thomas Meitinger^{48

49}, Lude Franke²¹, Till Roenneberg², Cornelia M van Duijn^{1

30

50}

Affiliations

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.

PMID: 27142678
PMCID: PMC5027680
DOI: 10.1038/ejhg.2016.31

Genetic variants in RBFOX3 are associated with sleep latency

Najaf Amin et al. Eur J Hum Genet. 2016 Oct.

. 2016 Oct;24(10):1488-95.

doi: 10.1038/ejhg.2016.31. Epub 2016 May 4.

Authors

Affiliations

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.

PMID: 27142678
PMCID: PMC5027680
DOI: 10.1038/ejhg.2016.31

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.

PubMed Disclaimer

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.

Figures

**Figure 1**
Regional association plot of sleep latency for the region 17q25. The plot was constructed using Locus Zoom (http://csg.sph.umich.edu/locuszoom/). The most significant SNP is depicted as a diamond and other SNPs in the region are depicted by circles. Various colors represent the extent of linkage disequilibrium with most significant SNP. The X axis gives the position in mega bases and the Y axis shows the negative logarithm of the P-values from the meta-analysis.

**Figure 2**
Means per genotype category for all the discovery cohorts for the three most significant SNPs. Black bars represent the mean sleep latency for the homozygous carriers of the effect allele. Y axis depicts the sleep latency time in minutes. Panels a, b and c represent the effects of the SNPs in individual cohorts. Panel d represents the pooled average sleep latency per genotype category across all cohorts for the three SNPs (X axis). Data used to generate this figure were not adjusted for age and sex.

**Figure 3**
Forest plot for the three SNPs at chromosome 17q25. On the left, the populations including the populations in the GWAS and the replication phase. The boxes represent the precision and horizontal lines representing the confidence intervals. Pooled estimate is the effect estimate from the meta-analysis of all cohorts. The horizontal axis represents the scale of effects.

See this image and copyright information in PMC

References

1. Krauchi K, Wirz-Justice A: Circadian clues to sleep onset mechanisms. Neuropsychopharmacology 2001; 25: S92–S96. - PubMed
1. Cirelli C: The genetic and molecular regulation of sleep: from fruit flies to humans. Nat Rev Neurosci 2009; 10: 549–560. - PMC - PubMed
1. Hastings M: The brain, circadian rhythms, and clock genes. BMJ 1998; 317: 1704–1707. - PMC - PubMed
1. Hastings MH: Central clocking. Trends Neurosci 1997; 20: 459–464. - PubMed
1. Baekeland F, Hoy P: Reported vs recorded sleep characteristics. Arch Gen Psychiatry 1971; 24: 548–551. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genetic variants in RBFOX3 are associated with sleep latency

Affiliations

Genetic variants in RBFOX3 are associated with sleep latency

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources