title: Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.
abstract: OBJECTIVE
  Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes.
  
  
  OBJECTIVE
  To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk.
  
  
  METHODS
  Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I.
  
  
  METHODS
  Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes.
  
  
  RESULTS
  Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture.
  
  
  CONCLUSIONS
  To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Scott C
authors: SC
authors: Fears
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Susan K
authors: SK
authors: Service
authors: Wellcome Trust Sanger Institute, Hinxton, England.
authors: Barbara
authors: B
authors: Kremeyer
authors: Cell and Molecular Biology Research, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors: Carmen
authors: C
authors: Araya
authors: Cell and Molecular Biology Research, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors: Xinia
authors: X
authors: Araya
authors: Cell and Molecular Biology Research, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors: Julio
authors: J
authors: Bejarano
authors: Cell and Molecular Biology Research, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors: Margarita
authors: M
authors: Ramirez
authors: Instituto de Alta Tecnología Médica de Antioquia, Medellín, Colombia.
authors: Gabriel
authors: G
authors: Castrillón
authors: Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
authors: Juliana
authors: J
authors: Gomez-Franco
authors: Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
authors: Maria C
authors: MC
authors: Lopez
authors: Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
authors: Gabriel
authors: G
authors: Montoya
authors: Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
authors: Patricia
authors: P
authors: Montoya
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Ileana
authors: I
authors: Aldana
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Terri M
authors: TM
authors: Teshiba
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Zvart
authors: Z
authors: Abaryan
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Noor B
authors: NB
authors: Al-Sharif
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Marissa
authors: M
authors: Ericson
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Maria
authors: M
authors: Jalbrzikowski
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles6Department of Psychiatry, ZNA Stuivenberg, Antwerp, Belgium.
authors: Jurjen J
authors: JJ
authors: Luykx
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Linda
authors: L
authors: Navarro
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Todd A
authors: TA
authors: Tishler
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Lori
authors: L
authors: Altshuler
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: George
authors: G
authors: Bartzokis
authors: Department of Psychiatry and Family Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick.
authors: Javier
authors: J
authors: Escobar
authors: Department of Psychiatry, Yale University, New Haven, Connecticut9Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut.
authors: David C
authors: DC
authors: Glahn
authors: Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
authors: Jorge
authors: J
authors: Ospina-Duque
authors: Institute for Human Genetics, University of California, San Francisco.
authors: Neil
authors: N
authors: Risch
authors: Department of Genetics, Evolution, and Environment, University College London, London, England.
authors: Andrés
authors: A
authors: Ruiz-Linares
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Paul M
authors: PM
authors: Thompson
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Rita M
authors: RM
authors: Cantor
authors: Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia12Mood Disorders Program, Hospital San Vicente Fundacion, Medellín, Colombia.
authors: Carlos
authors: C
authors: Lopez-Jaramillo
authors: Cell and Molecular Biology Research, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors: Gabriel
authors: G
authors: Macaya
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles13BioCiencias Lab, Guatemala, Guatemala.
authors: Julio
authors: J
authors: Molina
authors: Department of Psychiatry, University of California, San Francisco.
authors: Victor I
authors: VI
authors: Reus
authors: Department of Health Research and Policy, Stanford University, Stanford, California.
authors: Chiara
authors: C
authors: Sabatti
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Nelson B
authors: NB
authors: Freimer
authors: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.
authors: Carrie E
authors: CE
authors: Bearden
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D001921:Brain / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D009929:Organ Size / Q000502:physiology; D010375:Pedigree; D010641:Phenotype; D013223:Statistics as Topic; D013694:Temperament