Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders

Biol Psychiatry. 2011 Nov 1;70(9):888-96. doi: 10.1016/j.biopsych.2011.07.012. Epub 2011 Aug 25.


Background: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions.

Methods: We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression).

Results: Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing.

Conclusions: Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Twin Study

MeSH terms

  • Animals
  • Anxiety Disorders / genetics*
  • Behavior, Animal
  • Data Interpretation, Statistical
  • Databases, Genetic
  • Diagnostic and Statistical Manual of Mental Disorders
  • Fear / physiology
  • Fear / psychology
  • Genetic Linkage
  • Genome-Wide Association Study
  • Genotype
  • Heat-Shock Proteins / genetics
  • Humans
  • Mice
  • Mice, Knockout
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polymorphism, Single Nucleotide
  • Transcription Factors / genetics


  • Heat-Shock Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors