title: Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders.
abstract: 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.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298-0126, USA. jhettema@vcu.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Hettema
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Webb
authors.forename: An-Yuan
authors.initials: AY
authors.lastname: Guo
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
authors.forename: Seon-Sook
authors.initials: SS
authors.lastname: An
authors.forename: Cuie
authors.initials: C
authors.lastname: Sun
authors.forename: Steven H
authors.initials: SH
authors.lastname: Aggen
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.forename: Po-Hsiu
authors.initials: PH
authors.lastname: Kuo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otowa
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: van den Oord
mesh_terms: D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics*; D001522:Behavior, Animal; D003627:Data Interpretation, Statistical; D030541:Databases, Genetic; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005239:Fear / Q000502:physiology / Q000523:psychology; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors