Genetic variants in RBFOX3 are associated with sleep latency

Najaf Amin; Karla V Allebrandt; Ashley van der Spek; Bertram Müller-Myhsok; Karin Hek; Maris Teder-Laving; Caroline Hayward; Tõnu Esko; Josine G van Mill; Hamdi Mbarek; Nathaniel F Watson; Scott A Melville; Fabiola M Del Greco; Enda M Byrne; Edwin Oole; Ivana Kolcic; Ting-Hsu Chen; Daniel S Evans; Josef Coresh; Nicole Vogelzangs; Juha Karjalainen; Gonneke Willemsen; Sina A Gharib; Lina Zgaga; Evelin Mihailov; Katie L Stone; Harry Campbell; Rutger Ww Brouwer; Ayse Demirkan; Aaron Isaacs; Zoran Dogas; Kristin D Marciante; Susan Campbell; Fran Borovecki; Annemarie I Luik; Man Li; Jouke Jan Hottenga; Jennifer E Huffman; Mirjam Cgn van den Hout; Steven R Cummings; Yurii S Aulchenko; Philip R Gehrman; André G Uitterlinden; Heinz-Erich Wichmann; Martina Müller-Nurasyid; Rudolf Sn Fehrmann; Grant W Montgomery; Albert Hofman; Wen Hong Linda Kao; Ben A Oostra; Alan F Wright; Jacqueline M Vink; James F Wilson; Peter P Pramstaller; Andrew A Hicks; Ozren Polasek; Naresh M Punjabi; Susan Redline; Bruce M Psaty; Andrew C Heath; Martha Merrow; Gregory J Tranah; Daniel J Gottlieb; Dorret I Boomsma; Nicholas G Martin; Igor Rudan; Henning Tiemeier; Wilfred Fj van IJcken; Brenda W Penninx; Andres Metspalu; Thomas Meitinger; Lude Franke; Till Roenneberg; Cornelia M van Duijn

doi:10.1038/ejhg.2016.31

Genetic variants in RBFOX3 are associated with sleep latency

Najaf Amin^*, Karla V Allebrandt, Ashley van der Spek, Bertram Müller-Myhsok, Karin Hek, Maris Teder-Laving, Caroline Hayward, Tõnu Esko, Josine G van Mill, Hamdi Mbarek, Nathaniel F Watson, Scott A Melville, Fabiola M Del Greco, Enda M Byrne, Edwin Oole, Ivana Kolcic, Ting-Hsu Chen, Daniel S Evans, Josef Coresh, Nicole VogelzangsJuha Karjalainen, Gonneke Willemsen, Sina A Gharib, Lina Zgaga, Evelin Mihailov, Katie L Stone, Harry Campbell, Rutger Ww Brouwer, Ayse Demirkan, Aaron Isaacs, Zoran Dogas, Kristin D Marciante, Susan Campbell, Fran Borovecki, Annemarie I Luik, Man Li, Jouke Jan Hottenga, Jennifer E Huffman, Mirjam Cgn van den Hout, Steven R Cummings, Yurii S Aulchenko, Philip R Gehrman, André G Uitterlinden, Heinz-Erich Wichmann, Martina Müller-Nurasyid, Rudolf Sn Fehrmann, Grant W Montgomery, Albert Hofman, Wen Hong Linda Kao, Ben A Oostra, Alan F Wright, Jacqueline M Vink, James F Wilson, Peter P Pramstaller, Andrew A Hicks, Ozren Polasek, Naresh M Punjabi, Susan Redline, Bruce M Psaty, Andrew C Heath, Martha Merrow, Gregory J Tranah, Daniel J Gottlieb, Dorret I Boomsma, Nicholas G Martin, Igor Rudan, Henning Tiemeier, Wilfred Fj van IJcken, Brenda W Penninx, Andres Metspalu, Thomas Meitinger, Lude Franke, Till Roenneberg, Cornelia M van Duijn

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	1488-1495
Number of pages	8
Journal	European Journal of Human Genetics
Volume	24
Issue number	10
DOIs	https://doi.org/10.1038/ejhg.2016.31
Publication status	Published - Oct 2016

Keywords

GENOME-WIDE ASSOCIATION
LINKAGE ANALYSIS
ONSET INSOMNIA
RECORDED SLEEP
CANDIDATE-GENE
SELF-REPORT
EXPRESSION
FAMILY
DETERMINANTS
IMPUTATION

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10.1038/ejhg.2016.31

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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., ... 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

@article{6ffa1b6f8d844ef4bd3846a5f30c100f,

title = "Genetic variants in RBFOX3 are associated with sleep latency",

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.",

keywords = "GENOME-WIDE ASSOCIATION, LINKAGE ANALYSIS, ONSET INSOMNIA, RECORDED SLEEP, CANDIDATE-GENE, SELF-REPORT, EXPRESSION, FAMILY, DETERMINANTS, IMPUTATION",

author = "Najaf Amin and Allebrandt, {Karla V} and {van der Spek}, Ashley and Bertram M{\"u}ller-Myhsok and Karin Hek and Maris Teder-Laving and Caroline Hayward and T{\~o}nu Esko and {van Mill}, {Josine G} and Hamdi Mbarek and Watson, {Nathaniel F} and Melville, {Scott A} and {Del Greco}, {Fabiola M} and Byrne, {Enda M} and Edwin Oole and Ivana Kolcic and Ting-Hsu Chen and Evans, {Daniel S} and Josef Coresh and Nicole Vogelzangs and Juha Karjalainen and Gonneke Willemsen and Gharib, {Sina A} and Lina Zgaga and Evelin Mihailov and Stone, {Katie L} and Harry Campbell and Brouwer, {Rutger Ww} and Ayse Demirkan and Aaron Isaacs and Zoran Dogas and Marciante, {Kristin D} and Susan Campbell and Fran Borovecki and Luik, {Annemarie I} and Man Li and Hottenga, {Jouke Jan} and Huffman, {Jennifer E} and {van den Hout}, {Mirjam Cgn} and Cummings, {Steven R} and Aulchenko, {Yurii S} and Gehrman, {Philip R} and Uitterlinden, {Andr{\'e} G} and Heinz-Erich Wichmann and Martina M{\"u}ller-Nurasyid and Fehrmann, {Rudolf Sn} and Montgomery, {Grant W} and Albert Hofman and Kao, {Wen Hong Linda} and Oostra, {Ben A} and Wright, {Alan F} and Vink, {Jacqueline M} and Wilson, {James F} and Pramstaller, {Peter P} and Hicks, {Andrew A} and Ozren Polasek and Punjabi, {Naresh M} and Susan Redline and Psaty, {Bruce M} and Heath, {Andrew C} and Martha Merrow and Tranah, {Gregory J} and Gottlieb, {Daniel J} and Boomsma, {Dorret I} and Martin, {Nicholas G} and Igor Rudan and Henning Tiemeier and {van IJcken}, {Wilfred Fj} and Penninx, {Brenda W} and Andres Metspalu and Thomas Meitinger and Lude Franke and Till Roenneberg and {van Duijn}, {Cornelia M}",

year = "2016",

month = oct,

doi = "10.1038/ejhg.2016.31",

language = "English",

volume = "24",

pages = "1488--1495",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "10",

}

Amin, N, Allebrandt, KV, van der Spek, A, Müller-Myhsok, B, Hek, K, Teder-Laving, M, Hayward, C, Esko, T, van Mill, JG, Mbarek, H, Watson, NF, Melville, SA, Del Greco, FM, Byrne, EM, Oole, E, Kolcic, I, Chen, T-H, Evans, DS, Coresh, J, Vogelzangs, N, Karjalainen, J, Willemsen, G, Gharib, SA, Zgaga, L, Mihailov, E, Stone, KL, Campbell, H, Brouwer, RW, Demirkan, A, Isaacs, A, Dogas, Z, Marciante, KD, Campbell, S, Borovecki, F, Luik, AI, Li, M, Hottenga, JJ, Huffman, JE, van den Hout, MC, Cummings, SR, Aulchenko, YS, Gehrman, PR, Uitterlinden, AG, Wichmann, H-E, Müller-Nurasyid, M, Fehrmann, RS, Montgomery, GW, Hofman, A, Kao, WHL, Oostra, BA, Wright, AF, Vink, JM, Wilson, JF, Pramstaller, PP, Hicks, AA, Polasek, O, Punjabi, NM, Redline, S, Psaty, BM, Heath, AC, Merrow, M, Tranah, GJ, Gottlieb, DJ, Boomsma, DI, Martin, NG, Rudan, I, Tiemeier, H, van IJcken, WF, Penninx, BW, Metspalu, A, Meitinger, T, Franke, L, Roenneberg, T & van Duijn, CM 2016, 'Genetic variants in RBFOX3 are associated with sleep latency', European Journal of Human Genetics, vol. 24, no. 10, pp. 1488-1495. https://doi.org/10.1038/ejhg.2016.31

TY - JOUR

T1 - Genetic variants in RBFOX3 are associated with sleep latency

AU - Amin, Najaf

AU - Allebrandt, Karla V

AU - van der Spek, Ashley

AU - Müller-Myhsok, Bertram

AU - Hek, Karin

AU - Teder-Laving, Maris

AU - Hayward, Caroline

AU - Esko, Tõnu

AU - van Mill, Josine G

AU - Mbarek, Hamdi

AU - Watson, Nathaniel F

AU - Melville, Scott A

AU - Del Greco, Fabiola M

AU - Byrne, Enda M

AU - Oole, Edwin

AU - Kolcic, Ivana

AU - Chen, Ting-Hsu

AU - Evans, Daniel S

AU - Coresh, Josef

AU - Vogelzangs, Nicole

AU - Karjalainen, Juha

AU - Willemsen, Gonneke

AU - Gharib, Sina A

AU - Zgaga, Lina

AU - Mihailov, Evelin

AU - Stone, Katie L

AU - Campbell, Harry

AU - Brouwer, Rutger Ww

AU - Demirkan, Ayse

AU - Isaacs, Aaron

AU - Dogas, Zoran

AU - Marciante, Kristin D

AU - Campbell, Susan

AU - Borovecki, Fran

AU - Luik, Annemarie I

AU - Li, Man

AU - Hottenga, Jouke Jan

AU - Huffman, Jennifer E

AU - van den Hout, Mirjam Cgn

AU - Cummings, Steven R

AU - Aulchenko, Yurii S

AU - Gehrman, Philip R

AU - Uitterlinden, André G

AU - Wichmann, Heinz-Erich

AU - Müller-Nurasyid, Martina

AU - Fehrmann, Rudolf Sn

AU - Montgomery, Grant W

AU - Hofman, Albert

AU - Kao, Wen Hong Linda

AU - Oostra, Ben A

AU - Wright, Alan F

AU - Vink, Jacqueline M

AU - Wilson, James F

AU - Pramstaller, Peter P

AU - Hicks, Andrew A

AU - Polasek, Ozren

AU - Punjabi, Naresh M

AU - Redline, Susan

AU - Psaty, Bruce M

AU - Heath, Andrew C

AU - Merrow, Martha

AU - Tranah, Gregory J

AU - Gottlieb, Daniel J

AU - Boomsma, Dorret I

AU - Martin, Nicholas G

AU - Rudan, Igor

AU - Tiemeier, Henning

AU - van IJcken, Wilfred Fj

AU - Penninx, Brenda W

AU - Metspalu, Andres

AU - Meitinger, Thomas

AU - Franke, Lude

AU - Roenneberg, Till

AU - van Duijn, Cornelia M

PY - 2016/10

Y1 - 2016/10

N2 - 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.

AB - 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.

KW - GENOME-WIDE ASSOCIATION

KW - LINKAGE ANALYSIS

KW - ONSET INSOMNIA

KW - RECORDED SLEEP

KW - CANDIDATE-GENE

KW - SELF-REPORT

KW - EXPRESSION

KW - FAMILY

KW - DETERMINANTS

KW - IMPUTATION

U2 - 10.1038/ejhg.2016.31

DO - 10.1038/ejhg.2016.31

M3 - Article

C2 - 27142678

SN - 1018-4813

VL - 24

SP - 1488

EP - 1495

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 10

ER -