Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders. Academic Article uri icon


  • 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.

published proceedings

  • Biol Psychiatry

altmetric score

  • 1

author list (cited authors)

  • Hettema, J. M., Webb, B. T., Guo, A., Zhao, Z., Maher, B. S., Chen, X., ... van den Oord, E. J.

citation count

  • 27

complete list of authors

  • Hettema, John M||Webb, Bradley T||Guo, An-Yuan||Zhao, Zhongming||Maher, Brion S||Chen, Xiangning||An, Seon-Sook||Sun, Cuie||Aggen, Steven H||Kendler, Kenneth S||Kuo, Po-Hsiu||Otowa, Takeshi||Flint, Jonathan||van den Oord, Edwin J

publication date

  • November 2011