title: Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder.
abstract: Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Lucia
authors.initials: L
authors.lastname: Pagani
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: St Clair
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Terri M
authors.initials: TM
authors.lastname: Teshiba
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Susan K
authors.initials: SK
authors.lastname: Service
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Scott C
authors.initials: SC
authors.lastname: Fears
authors.affiliation: Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
authors.forename: Carmen
authors.initials: C
authors.lastname: Araya
authors.affiliation: Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
authors.forename: Xinia
authors.initials: X
authors.lastname: Araya
authors.affiliation: Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
authors.forename: Julio
authors.initials: J
authors.lastname: Bejarano
authors.affiliation: Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
authors.forename: Margarita
authors.initials: M
authors.lastname: Ramirez
authors.affiliation: Instituto de Alta Tecnología Médica de Antioquia, Medellín, Colombia 050026;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Castrillón
authors.affiliation: Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
authors.forename: Juliana
authors.initials: J
authors.lastname: Gomez-Makhinson
authors.affiliation: Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lopez
authors.affiliation: Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Montoya
authors.affiliation: Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Montoya
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Ileana
authors.initials: I
authors.lastname: Aldana
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Linda
authors.initials: L
authors.lastname: Navarro
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Freimer
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Brian
authors.initials: B
authors.lastname: Safaie
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Lap-Woon
authors.initials: LW
authors.lastname: Keung
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Kiefer
authors.initials: K
authors.lastname: Greenspan
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Katty
authors.initials: K
authors.lastname: Chou
authors.affiliation: Department of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901;
authors.forename: Javier I
authors.initials: JI
authors.lastname: Escobar
authors.affiliation: Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
authors.forename: Jorge
authors.initials: J
authors.lastname: Ospina-Duque
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Barbara
authors.initials: B
authors.lastname: Kremeyer
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Andres
authors.initials: A
authors.lastname: Ruiz-Linares
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.affiliation: Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011; Mood Disorders Program, Hospital San Vicente Fundacion, Medellín, Colombia 050011;
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Jaramillo
authors.affiliation: Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Macaya
authors.affiliation: BioCiencias Lab, 01010 Guatemala, Guatemala;
authors.forename: Julio
authors.initials: J
authors.lastname: Molina
authors.affiliation: Department of Psychiatry, University of California, San Francisco, CA 94143;
authors.forename: Victor I
authors.initials: VI
authors.lastname: Reus
authors.affiliation: Department of Health Research and Policy, Division of Biostatistics, Stanford University, Stanford, CA 94305;
authors.forename: Chiara
authors.initials: C
authors.lastname: Sabatti
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Bearden
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 joseph.takahashi@utsouthwestern.edu nfreimer@mednet.ucla.edu.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095; joseph.takahashi@utsouthwestern.edu nfreimer@mednet.ucla.edu.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
mesh_terms: D056044:Actigraphy; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002940:Circadian Rhythm; D005190:Family; D005260:Female; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D012890:Sleep
keywords: actigraphy; behavior; bipolar disorder; circadian rhythms; endophenotypes