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.
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.
Authors: J F Scherrer; W R True; H Xian; M J Lyons; S A Eisen; J Goldberg; N Lin; M T Tsuang Journal: J Affect Disord Date: 2000 Jan-Mar Impact factor: 4.839
Authors: William Valdar; Leah C Solberg; Dominique Gauguier; Stephanie Burnett; Paul Klenerman; William O Cookson; Martin S Taylor; J Nicholas P Rawlins; Richard Mott; Jonathan Flint Journal: Nat Genet Date: 2006-07-09 Impact factor: 38.330
Authors: Julie St-Pierre; Stavit Drori; Marc Uldry; Jessica M Silvaggi; James Rhee; Sibylle Jäger; Christoph Handschin; Kangni Zheng; Jiandie Lin; Wenli Yang; David K Simon; Robert Bachoo; Bruce M Spiegelman Journal: Cell Date: 2006-10-20 Impact factor: 41.582
Authors: Ronald C Kessler; Patricia Berglund; Olga Demler; Robert Jin; Kathleen R Merikangas; Ellen E Walters Journal: Arch Gen Psychiatry Date: 2005-06
Authors: Jonas Donner; Sami Pirkola; Kaisa Silander; Laura Kananen; Joseph D Terwilliger; Jouko Lönnqvist; Leena Peltonen; Iiris Hovatta Journal: Biol Psychiatry Date: 2008-07-17 Impact factor: 13.382
Authors: Clarissa C Parker; Peter Carbonetto; Greta Sokoloff; Yeonhee J Park; Mark Abney; Abraham A Palmer Journal: Genetics Date: 2014-09 Impact factor: 4.562
Authors: John M Hettema; Brad Verhulst; Chris Chatzinakos; Silviu-Alin Bacanu; Chia-Yen Chen; Robert J Ursano; Ronald C Kessler; Joel Gelernter; Jordan W Smoller; Feng He; Sonia Jain; Murray B Stein Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2019-12-30 Impact factor: 3.568
Authors: Takeshi Otowa; Brion S Maher; Steven H Aggen; Joseph L McClay; Edwin J van den Oord; John M Hettema Journal: PLoS One Date: 2014-11-12 Impact factor: 3.240
Authors: Aundrea F Bartley; Elizabeth K Lucas; Lillian J Brady; Qin Li; John J Hablitz; Rita M Cowell; Lynn E Dobrunz Journal: J Neurosci Date: 2015-11-18 Impact factor: 6.167