title: Direct, indirect and pleiotropic effects of candidate genes on internalizing disorder psychopathology.
abstract: BACKGROUND
  Twin studies of internalizing disorders suggest that their high co-morbidity is partially explained by shared genetic risk. Few studies have investigated pleiotropic effects of well-validated candidate genes across phenotypes.
  
  
  METHODS
  Subjects were 928 Caucasian patients who presented to an out-patient clinic specializing in the assessment and treatment of anxiety and mood disorders. We constructed latent dimensional phenotypes across the internalizing spectrum (neuroticism, extraversion, depression, generalized anxiety, panic/agoraphobia, social phobia, post-traumatic stress, and obsessions-compulsions) by combining diagnostic criteria with other clinical indicators. We selected multiple variants in four evidence-based candidate genes (SLC6A4, COMT, GAD1, RGS2) with previously reported effects on several of these phenotypes. We conducted genetic association testing of their direct and indirect effects as well as gene × stress interactions (G × E).
  
  
  RESULTS
  We detected 19 nominally significant main effect associations for the 10 polymorphisms tested among the eight phenotypes (24%). These were generally phenotype non-specific, showing pleiotropic effects across multiple domains. The majority of observed sharing was between depression, panic disorder, and post-traumatic stress disorder. Some of these were best explained by mediational models in which genes increase liability for disorders indirectly via their effects on temperament. Limited G × E effects were detected between variants in SLC6A4 and both panic/agoraphobia and post-traumatic stress.
  
  
  CONCLUSIONS
  Examining just a few candidate genes for their potential roles in internalizing phenotypes, we found moderate support for the shared effects of several polymorphisms. These findings highlight the richness and complexity by which genes potentially contribute to psychopathology via pleiotropy, moderation by stress, and mediation by temperament.
authors.affiliation: Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University,Richmond,VA,USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Hettema
authors.affiliation: Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University,Richmond,VA,USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Psychiatry,Virginia Institute for Psychiatric and Behavioral Genetics,Virginia Commonwealth University,Richmond,VA,USA.
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Psychology,Center for Anxiety and Related Disorders,Boston University,Boston,MA,USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001008:Anxiety Disorders / Q000235:genetics* / Q000523:psychology*; D001900:Boston / Q000453:epidemiology; D002394:Catechol O-Methyltransferase / Q000235:genetics; D005260:Female; D059647:Gene-Environment Interaction; D005968:Glutamate Decarboxylase / Q000235:genetics; D006801:Humans; D007406:Interview, Psychological; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology*; D010641:Phenotype; D000072861:Phobia, Social / Q000453:epidemiology; D011110:Polymorphism, Genetic; D011599:Psychopathology; D020710:RGS Proteins / Q000235:genetics; D012044:Regression Analysis; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013315:Stress, Psychological; D044465:White People; D055815:Young Adult
chemical_list: D020710:RGS Proteins; C087182:RGS2 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: Anxiety disorder; candidate genes; depression; genetic associations; structural equation modeling; temperament