Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 24, Issue 10, Pages 1488-1495Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2016.31
Keywords
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Funding
- FP6 programme EUCLOCK
- Dutch Science Foundation (the NWO)
- Hersenstichting Nederland
- Rosalind Franklin Fellowships of the University of Groningen
- Estonian Government
- European Union through the European Regional Development Fund in the frame of Centre of Excellence in Genomics
- Geestkracht programme of the Dutch Scientific Organization (ZON-MW)
- Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health
- EUROSPAN (European Special Populations Research Network) through the European Commission FP6 STRP grant
- Chief Scientist Office of the Scottish Government
- Royal Society
- Centre for Medical Systems Biology [CMSB1, CMSB2]
- Netherlands Genomics Initiative (NGI)
- Netherlands Organization for Scientific Research (NWO-VENI) [916.10.135]
- Netherlands Genomics Initiative [92519031]
- European Community's Health Seventh Framework Programme (FP7) [259867]
- FP7 Projects ECOGENE
- BBMRI
- ENGAGE
- OPENGENE
- Medical Research Council, Erasmus University, Erasmus MC
- ALBAN
- MRC [MC_PC_U127561128] Funding Source: UKRI
- Medical Research Council [MC_PC_U127561128] Funding Source: researchfish
- Parkinson's UK [K-1206] Funding Source: researchfish
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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 x 10(-08), 6.59 x 10(-08) and 9.17 x 10(-08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values = 1.5 x 10(-02), 7.0 x 10(-03) and 2.5 x 10(-03); combined meta-analysis P-values = 5.5 x 10(-07), 5.4 x 10(-07) and 1.0 x 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 x 10(-316)) and the central nervous system (P-value = 7.5 x 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<2.9x10(-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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