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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.

Original publication

DOI

10.1016/j.biopsych.2011.07.012

Type

Journal article

Journal

Biol Psychiatry

Publication Date

01/11/2011

Volume

70

Pages

888 - 896

Keywords

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