A genome-wide association study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor

Sleep. 2012 Jul 1;35(7):967-75. doi: 10.5665/sleep.1962.


Objectives: To identify common genetic variants that predispose to caffeine-induced insomnia and to test whether genes whose expression changes in the presence of caffeine are enriched for association with caffeine-induced insomnia.

Design: A hypothesis-free, genome-wide association study.

Setting: Community-based sample of Australian twins from the Australian Twin Registry.

Participants: After removal of individuals who said that they do not drink coffee, a total of 2,402 individuals from 1,470 families in the Australian Twin Registry provided both phenotype and genotype information.

Measurements and results: A dichotomized scale based on whether participants reported ever or never experiencing caffeine-induced insomnia. A factor score based on responses to a number of questions regarding normal sleep habits was included as a covariate in the analysis. More than 2 million common single nucleotide polymorphisms (SNPs) were tested for association with caffeine-induced insomnia. No SNPs reached the genome-wide significance threshold. In the analysis that did not include the insomnia factor score as a covariate, the most significant SNP identified was an intronic SNP in the PRIMA1 gene (P = 1.4 × 10⁻⁶, odds ratio = 0.68 [0.53 - 0.89]). An intergenic SNP near the GBP4 gene on chromosome 1 was the most significant upon inclusion of the insomnia factor score into the model (P = 1.9 × 10⁻⁶, odds ratio = 0.70 [0.62 - 0.78]). A previously identified association with a polymorphism in the ADORA2A gene was replicated.

Conclusions: Several genes have been identified in the study as potentially influencing caffeine-induced insomnia. They will require replication in another sample. The results may have implications for understanding the biologic mechanisms underlying insomnia.

Keywords: Caffeine; genetics; insomnia.

Publication types

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

MeSH terms

  • Adult
  • Caffeine / adverse effects*
  • Female
  • Gene Expression Profiling
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Polymorphism, Single Nucleotide / genetics*
  • Receptor, Adenosine A2A / genetics*
  • Receptor, Adenosine A2A / physiology
  • Sleep Wake Disorders / chemically induced
  • Sleep Wake Disorders / genetics*


  • Membrane Proteins
  • Nerve Tissue Proteins
  • PRIMA1 protein, human
  • Receptor, Adenosine A2A
  • Caffeine