Scott C Fears1, Susan K Service1, Barbara Kremeyer2, Carmen Araya3, Xinia Araya3, Julio Bejarano3, Margarita Ramirez3, Gabriel Castrillón4, Juliana Gomez-Franco5, Maria C Lopez5, Gabriel Montoya5, Patricia Montoya5, Ileana Aldana1, Terri M Teshiba1, Zvart Abaryan1, Noor B Al-Sharif1, Marissa Ericson1, Maria Jalbrzikowski1, Jurjen J Luykx6, Linda Navarro1, Todd A Tishler1, Lori Altshuler1, George Bartzokis1, Javier Escobar7, David C Glahn8, Jorge Ospina-Duque5, Neil Risch9, Andrés Ruiz-Linares10, Paul M Thompson1, Rita M Cantor1, Carlos Lopez-Jaramillo11, Gabriel Macaya3, Julio Molina12, Victor I Reus13, Chiara Sabatti14, Nelson B Freimer1, Carrie E Bearden1. 1. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles. 2. Wellcome Trust Sanger Institute, Hinxton, England. 3. Cell and Molecular Biology Research, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica. 4. Instituto de Alta Tecnología Médica de Antioquia, Medellín, Colombia. 5. Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia. 6. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles6Department of Psychiatry, ZNA Stuivenberg, Antwerp, Belgium. 7. Department of Psychiatry and Family Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick. 8. Department of Psychiatry, Yale University, New Haven, Connecticut9Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut. 9. Institute for Human Genetics, University of California, San Francisco. 10. Department of Genetics, Evolution, and Environment, University College London, London, England. 11. Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia12Mood Disorders Program, Hospital San Vicente Fundacion, Medellín, Colombia. 12. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles13BioCiencias Lab, Guatemala, Guatemala. 13. Department of Psychiatry, University of California, San Francisco. 14. Department of Health Research and Policy, Stanford University, Stanford, California.
Abstract
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.
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