A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila

Mol Psychiatry. 2013 Jan;18(1):122-32. doi: 10.1038/mp.2011.142. Epub 2011 Nov 22.

Abstract

Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 × 10(-8)) in the ABCC9 gene that explains ≈5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Animals, Genetically Modified
  • Cohort Studies
  • Drosophila / genetics
  • Drosophila / physiology
  • Drosophila Proteins / genetics
  • European Continental Ancestry Group
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Kv1.3 Potassium Channel / genetics*
  • Male
  • Middle Aged
  • Myocardium / metabolism
  • Myocardium / pathology
  • Phenotype
  • Photoperiod
  • Plakophilins / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Potassium Channels, Inwardly Rectifying / genetics
  • RNA Interference / physiology
  • Receptors, Drug / genetics
  • Repressor Proteins / genetics
  • Sleep Wake Disorders / genetics*
  • Sulfonylurea Receptors
  • Young Adult

Substances

  • ABCC9 protein, human
  • ATP-Binding Cassette Transporters
  • Drosophila Proteins
  • KCNAB1 protein, human
  • Kv1.3 Potassium Channel
  • PKP2 protein, human
  • Plakophilins
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Repressor Proteins
  • Sulfonylurea Receptors
  • pan protein, Drosophila