Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci

Samuel E. Jones, Jessica Tyrrell, Andrew R. Wood, Robin N. Beaumont, Katherine S. Ruth, Marcus A. Tuke, Hanieh Yaghootkar, Youna Hu, Maris Teder-Laving, Caroline Hayward, Till Roenneberg, James F. Wilson, Fabiola Del Greco, Andrew A. Hicks, Chol Shin, Chang Ho Yun, Seung Ku Lee, Andres Metspalu, Enda M. Byrne, Philip R. GehrmanHenning Tiemeier, Karla V. Allebrandt, Rachel M. Freathy, Anna Murray, David A. Hinds, Timothy M. Frayling, Michael N. Weedon

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

Original languageEnglish
Article numbere1006125
JournalPLoS Genetics
Volume12
Issue number8
DOIs
Publication statusPublished - 2016 Aug 1

Fingerprint

sleep
Genome-Wide Association Study
Sleep
genome
circadian rhythm
loci
duration
Circadian Rhythm
allele
diabetes
Alleles
meta-analysis
alleles
noninsulin-dependent diabetes mellitus
Mendelian Randomization Analysis
Type 2 Diabetes Mellitus
Meta-Analysis
obesity
Iris
human diseases

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Jones, S. E., Tyrrell, J., Wood, A. R., Beaumont, R. N., Ruth, K. S., Tuke, M. A., ... Weedon, M. N. (2016). Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. PLoS Genetics, 12(8), [e1006125]. https://doi.org/10.1371/journal.pgen.1006125

Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. / Jones, Samuel E.; Tyrrell, Jessica; Wood, Andrew R.; Beaumont, Robin N.; Ruth, Katherine S.; Tuke, Marcus A.; Yaghootkar, Hanieh; Hu, Youna; Teder-Laving, Maris; Hayward, Caroline; Roenneberg, Till; Wilson, James F.; Del Greco, Fabiola; Hicks, Andrew A.; Shin, Chol; Yun, Chang Ho; Lee, Seung Ku; Metspalu, Andres; Byrne, Enda M.; Gehrman, Philip R.; Tiemeier, Henning; Allebrandt, Karla V.; Freathy, Rachel M.; Murray, Anna; Hinds, David A.; Frayling, Timothy M.; Weedon, Michael N.

In: PLoS Genetics, Vol. 12, No. 8, e1006125, 01.08.2016.

Research output: Contribution to journalArticle

Jones, SE, Tyrrell, J, Wood, AR, Beaumont, RN, Ruth, KS, Tuke, MA, Yaghootkar, H, Hu, Y, Teder-Laving, M, Hayward, C, Roenneberg, T, Wilson, JF, Del Greco, F, Hicks, AA, Shin, C, Yun, CH, Lee, SK, Metspalu, A, Byrne, EM, Gehrman, PR, Tiemeier, H, Allebrandt, KV, Freathy, RM, Murray, A, Hinds, DA, Frayling, TM & Weedon, MN 2016, 'Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci', PLoS Genetics, vol. 12, no. 8, e1006125. https://doi.org/10.1371/journal.pgen.1006125
Jones, Samuel E. ; Tyrrell, Jessica ; Wood, Andrew R. ; Beaumont, Robin N. ; Ruth, Katherine S. ; Tuke, Marcus A. ; Yaghootkar, Hanieh ; Hu, Youna ; Teder-Laving, Maris ; Hayward, Caroline ; Roenneberg, Till ; Wilson, James F. ; Del Greco, Fabiola ; Hicks, Andrew A. ; Shin, Chol ; Yun, Chang Ho ; Lee, Seung Ku ; Metspalu, Andres ; Byrne, Enda M. ; Gehrman, Philip R. ; Tiemeier, Henning ; Allebrandt, Karla V. ; Freathy, Rachel M. ; Murray, Anna ; Hinds, David A. ; Frayling, Timothy M. ; Weedon, Michael N. / Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. In: PLoS Genetics. 2016 ; Vol. 12, No. 8.
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AU - Ruth, Katherine S.

AU - Tuke, Marcus A.

AU - Yaghootkar, Hanieh

AU - Hu, Youna

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AU - Roenneberg, Till

AU - Wilson, James F.

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AU - Allebrandt, Karla V.

AU - Freathy, Rachel M.

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AU - Hinds, David A.

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N2 - Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

AB - Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

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