Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly

Daniel S. Evans, Neeta Parimi, Caroline M. Nievergelt, Terri Blackwell, Susan Redline, Sonia Ancoli-Israel, Eric S. Orwoll, Steven R. Cummings, Katie L. Stone, Gregory J. Tranah

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33 Scopus citations

Abstract

Study Objectives: To determine the association between common genetic variation in the clock gene pathway and objectively measured actigraphic sleep and activity rhythm traits. Design: 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. Setting: Population-based. Participants: 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. Interventions: N/A. Measurements and 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.

Original languageEnglish (US)
Pages (from-to)431-446
Number of pages16
JournalSleep
Volume36
Issue number3
DOIs
StatePublished - Mar 1 2013

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Keywords

  • Actigraphy
  • Aging
  • Circadian
  • Genetic
  • SNP

ASJC Scopus subject areas

  • Clinical Neurology
  • Physiology (medical)

Cite this

Evans, D. S., Parimi, N., Nievergelt, C. M., Blackwell, T., Redline, S., Ancoli-Israel, S., Orwoll, E. S., Cummings, S. R., Stone, K. L., & Tranah, G. J. (2013). Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. Sleep, 36(3), 431-446. https://doi.org/10.5665/sleep.2466