title: Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci.
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.
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Samuel E
authors: SE
authors: Jones
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Jessica
authors: J
authors: Tyrrell
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Andrew R
authors: http://orcid.org/0000-0003-1726-948X
authors: AR
authors: Wood
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Robin N
authors: http://orcid.org/0000-0003-0750-8248
authors: RN
authors: Beaumont
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Katherine S
authors: http://orcid.org/0000-0003-4966-9170
authors: KS
authors: Ruth
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Marcus A
authors: MA
authors: Tuke
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Hanieh
authors: H
authors: Yaghootkar
authors: 23andMe Inc., Mountain View, California, United States of America.|A9.com Inc, Palo Alto, California, United States of America.
authors: Youna
authors: Y
authors: Hu
authors: Estonian Genome Center and Institute of Molecular and Cell Biology of University of Tartu, Estonian Biocentre, Tartu, Estonia.
authors: Maris
authors: M
authors: Teder-Laving
authors: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, Scotland.
authors: Caroline
authors: C
authors: Hayward
authors: Institute of Medical Psychology, Ludwig-Maximilians-University, Munich, Germany.
authors: Till
authors: T
authors: Roenneberg
authors: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, Scotland.|Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
authors: James F
authors: http://orcid.org/0000-0001-5751-9178
authors: JF
authors: Wilson
authors: Center for Biomedicine, European Academy of Bolzano, Bozen, Italy-affiliated Institute of the University of Lübeck, Lübeck, Germany.
authors: Fabiola
authors: F
authors: Del Greco
authors: Center for Biomedicine, European Academy of Bolzano, Bozen, Italy-affiliated Institute of the University of Lübeck, Lübeck, Germany.
authors: Andrew A
authors: AA
authors: Hicks
authors: Division of Pulmonary, Sleep and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.|Institute of Human Genomic Study, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
authors: Chol
authors: C
authors: Shin
authors: Department of Neurology, Bundang Clinical Neuroscience Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Chang-Ho
authors: http://orcid.org/0000-0003-2204-8067
authors: CH
authors: Yun
authors: Institute of Human Genomic Study, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
authors: Seung Ku
authors: http://orcid.org/0000-0002-6857-9747
authors: SK
authors: Lee
authors: Estonian Genome Center and Institute of Molecular and Cell Biology of University of Tartu, Estonian Biocentre, Tartu, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: The University of Queensland, Queensland Brain Institute, Brisbane, Australia.
authors: Enda M
authors: EM
authors: Byrne
authors: Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Philip R
authors: PR
authors: Gehrman
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.|Department of Psychiatry, Erasmus Medical Center, Rotterdam, Netherlands.
authors: Henning
authors: H
authors: Tiemeier
authors: Institute of Medical Psychology, Ludwig-Maximilians-University, Munich, Germany.
authors: Karla V
authors: KV
authors: Allebrandt
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Rachel M
authors: http://orcid.org/0000-0003-4152-2238
authors: RM
authors: Freathy
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Anna
authors: A
authors: Murray
authors: 23andMe Inc., Mountain View, California, United States of America.
authors: David A
authors: DA
authors: Hinds
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Timothy M
authors: http://orcid.org/0000-0001-8362-2603
authors: TM
authors: Frayling
authors: Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
authors: Michael N
authors: MN
authors: Weedon
mesh_terms: D015992:Body Mass Index; D002940:Circadian Rhythm / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D009765:Obesity / Q000235:genetics / Q000473:pathology; D000072636:PAX8 Transcription Factor / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012890:Sleep / Q000235:genetics* / Q000502:physiology; D044465:White People
chemical_list: D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D017346:Protein Serine-Threonine Kinases; C109891:VRK2 protein, human