title: Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.
abstract: The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.
authors: Center for Human Genetic Research and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA.
authors: Jacqueline M
authors: JM
authors: Lane
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA Department of Biobehavioral Health, Pennsylvania State University, University Park, PA.
authors: Anne-Marie
authors: AM
authors: Chang
authors: Center for Human Genetic Research and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA.
authors: Andrew C
authors: AC
authors: Bjonnes
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany.
authors: Daniel
authors: D
authors: Aeschbach
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Clare
authors: C
authors: Anderson
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Brian E
authors: BE
authors: Cade
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Sean W
authors: SW
authors: Cain
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Charles A
authors: CA
authors: Czeisler
authors: Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA.
authors: Sina A
authors: SA
authors: Gharib
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Joshua J
authors: JJ
authors: Gooley
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Daniel J
authors: DJ
authors: Gottlieb
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA.
authors: Struan F A
authors: SF
authors: Grant
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Elizabeth B
authors: EB
authors: Klerman
authors: Department of Health Studies, The University of Chicago, Chicago, IL.
authors: Diane S
authors: DS
authors: Lauderdale
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia.
authors: Steven W
authors: SW
authors: Lockley
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Miriam
authors: M
authors: Munch
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Sanjay
authors: S
authors: Patel
authors: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD.
authors: Naresh M
authors: NM
authors: Punjabi
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Shanthakumar M W
authors: SM
authors: Rajaratnam
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Melanie
authors: M
authors: Rueger
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Melissa A
authors: MA
authors: St Hilaire
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Nayantara
authors: N
authors: Santhi
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Karin
authors: K
authors: Scheuermaier
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Eliza
authors: E
authors: Van Reen
authors: The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors: Phyllis C
authors: PC
authors: Zee
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Steven A
authors: SA
authors: Shea
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Jeanne F
authors: JF
authors: Duffy
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA Department of Biobehavioral Health, Pennsylvania State University, University Park, PA Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, MA.
authors: Orfeu M
authors: OM
authors: Buxton
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Susan
authors: S
authors: Redline
authors: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.
authors: Frank A J L
authors: FA
authors: Scheer
authors: Center for Human Genetic Research and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA rsaxena@broadinstitute.org.
authors: Richa
authors: R
authors: Saxena
mesh_terms: D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000032:analysis; D002940:Circadian Rhythm / Q000235:genetics*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D005215:Fasting / Q000097:blood; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008550:Melatonin / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D012307:Risk Factors; D012890:Sleep / Q000235:genetics*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; C573871:MTNR1B protein, human; D044123:Receptor, Melatonin, MT2; D008550:Melatonin