title: Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly.
abstract: OBJECTIVE
  To determine the association between common genetic variation in the clock gene pathway and objectively measured acti-graphic sleep and activity rhythm traits.
  
  
  METHODS
  Genetic association study in two population-based cohorts of elderly participants: the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men (MrOS) study.
  
  
  METHODS
  Population-based.
  
  
  METHODS
  SOF participants (n = 1,407, 100% female, mean age 84 years) and MrOS participants (n = 2,527, 100% male, mean age 77 years) with actigraphy and genotype data.
  
  
  METHODS
  N/A.
  
  
  RESULTS
  Common genetic variation in 30 candidate genes was captured using 529 single nucleotide polymorphisms (SNPs). Sleep and activity rhythm traits were objectively measured using wrist actigraphy. In a region of high linkage disequilibrium on chromosome 12p13 containing the candidate gene GNB3, the rs1047776 A allele and the rs2238114 C allele were significantly associated with higher wake after sleep onset (meta-analysis: rs1047776 PADD = 2 × 10(-5), rs2238114 PADD = 5 × 10(-5)) and lower LRRC23 gene expression (rs1047776: ρ = -0.22, P = 0.02; rs2238114: ρ = -0.50, P = 5 × 10(-8)). In MrOS participants, SNPs in ARNTL and NPAS2, genes coding for binding partners, were associated with later sleep and wake onset time (sleep onset time: ARNTL rs3816358 P2DF = 1 × 10(-4), NPAS2 rs3768984 P2DF = 5 × 10(-5); wake onset time: rs3816358 P2DF = 3 × 10(-3), rs3768984 P2DF = 2 × 10(-4)) and the SNP interaction was significant (sleep onset time PINT = 0.003, wake onset time PINT = 0.001). A SNP association in the CLOCK gene replicated in the MrOS cohort, and rs3768984 was associated with sleep duration in a previously reported study. Cluster analysis identified four clusters of genetic associations.
  
  
  CONCLUSIONS
  These findings support a role for common genetic variation in clock genes in the regulation of inter-related sleep traits in the elderly.
  
  
  BACKGROUND
  Evans DS; Parimi N; Nievergelt CM; Blackwell T; Redline S; Ancoli-Israel S; Orwoll ES; Cummings SR; Stone KL; Tranah GJ. Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. SLEEP 2013;36(3):431-446.
authors: California Pacific Medical Center Research Institute, San Francisco, CA 94107-1728, USA.
authors: Daniel S
authors: DS
authors: Evans
authors: Neeta
authors: N
authors: Parimi
authors: Caroline M
authors: CM
authors: Nievergelt
authors: Terri
authors: T
authors: Blackwell
authors: Susan
authors: S
authors: Redline
authors: Sonia
authors: S
authors: Ancoli-Israel
authors: Eric S
authors: ES
authors: Orwoll
authors: Steven R
authors: SR
authors: Cummings
authors: Katie L
authors: KL
authors: Stone
authors: Gregory J
authors: GJ
authors: Tranah
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D056044:Actigraphy / Q000379:methods; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D015577:Geriatric Assessment / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017286:Polysomnography / Q000379:methods; D012890:Sleep / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000235:genetics*
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C538960:BMAL1 protein, human; C104264:NPAS2 protein, human
keywords: Genetic; SNP; actigraphy; aging; circadian