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Research Article

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder

Lucia Pagani, Patricia A. St. Clair, Terri M. Teshiba, Susan K. Service, Scott C. Fears, Carmen Araya, Xinia Araya, Julio Bejarano, Margarita Ramirez, Gabriel Castrillón, Juliana Gomez-Makhinson, Maria C. Lopez, Gabriel Montoya, Claudia P. Montoya, Ileana Aldana, Linda Navarro, Daniel G. Freimer, Brian Safaie, Lap-Woon Keung, Kiefer Greenspan, Katty Chou, Javier I. Escobar, Jorge Ospina-Duque, Barbara Kremeyer, Andres Ruiz-Linares, Rita M. Cantor, Carlos Lopez-Jaramillo, Gabriel Macaya, Julio Molina, Victor I. Reus, Chiara Sabatti, Carrie E. Bearden, Joseph S. Takahashi, and Nelson B. Freimer
  1. aDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390;
  2. bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
  3. cCell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
  4. dInstituto de Alta Tecnología Médica de Antioquia, Medellín, Colombia 050026;
  5. eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
  6. fDepartment of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901;
  7. gDepartment of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
  8. hMood Disorders Program, Hospital San Vicente Fundacion, Medellín, Colombia 050011;
  9. iBioCiencias Lab, 01010 Guatemala, Guatemala;
  10. jDepartment of Psychiatry, University of California, San Francisco, CA 94143;
  11. kDepartment of Health Research and Policy, Division of Biostatistics, Stanford University, Stanford, CA 94305;
  12. lHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390

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PNAS first published December 28, 2015; https://doi.org/10.1073/pnas.1513525113
Lucia Pagani
aDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390;
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Patricia A. St. Clair
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Terri M. Teshiba
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Susan K. Service
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Scott C. Fears
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Carmen Araya
cCell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
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Xinia Araya
cCell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
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Julio Bejarano
cCell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
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Margarita Ramirez
cCell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
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Gabriel Castrillón
dInstituto de Alta Tecnología Médica de Antioquia, Medellín, Colombia 050026;
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Juliana Gomez-Makhinson
eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
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Maria C. Lopez
eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
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Gabriel Montoya
eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
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Claudia P. Montoya
eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
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Ileana Aldana
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Linda Navarro
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Daniel G. Freimer
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Brian Safaie
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Lap-Woon Keung
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Kiefer Greenspan
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Katty Chou
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Javier I. Escobar
fDepartment of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901;
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Jorge Ospina-Duque
eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
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Barbara Kremeyer
gDepartment of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
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Andres Ruiz-Linares
gDepartment of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom;
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Rita M. Cantor
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Carlos Lopez-Jaramillo
eGrupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia 050011;
hMood Disorders Program, Hospital San Vicente Fundacion, Medellín, Colombia 050011;
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Gabriel Macaya
cCell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, Costa Rica 11501;
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Julio Molina
iBioCiencias Lab, 01010 Guatemala, Guatemala;
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Victor I. Reus
jDepartment of Psychiatry, University of California, San Francisco, CA 94143;
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Chiara Sabatti
kDepartment of Health Research and Policy, Division of Biostatistics, Stanford University, Stanford, CA 94305;
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Carrie E. Bearden
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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Joseph S. Takahashi
aDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390;
lHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
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  • For correspondence: joseph.takahashi@utsouthwestern.edu nfreimer@mednet.ucla.edu
Nelson B. Freimer
bDepartment of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
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  • For correspondence: joseph.takahashi@utsouthwestern.edu nfreimer@mednet.ucla.edu
  1. Contributed by Joseph S. Takahashi, November 24, 2015 (sent for review September 21, 2015; reviewed by Maja Bucan, Kathleen Ries Merikangas, and Emmanuel J. M. Mignot)

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Significance

Characterizing the abnormalities in sleep and activity that are associated with bipolar disorder (BP) and identifying their causation are key milestones in unraveling the biological underpinnings of this severe and highly prevalent disorder. We have conducted the first systematic evaluation of sleep and activity phenotypes in pedigrees that include multiple BP-affected members. By delineating specific sleep and activity measures that are significantly heritable in these families, and those whose variation correlated with the BP status of their members, and by determining the chromosomal position of loci contributing to many of these traits, we have taken the first step toward discovery of causative genetic variants. These variants, in turn, could provide clues to new approaches for both preventing and treating BP.

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.

  • bipolar disorder
  • endophenotypes
  • circadian rhythms
  • actigraphy
  • behavior

Footnotes

  • ↵1To whom correspondence may be addressed. Email: joseph.takahashi{at}utsouthwestern.edu or nfreimer{at}mednet.ucla.edu.
  • Author contributions: L.P., P.A.S.C., J.I.E., J.O.-D., B.K., A.R.-L., C.L.-J., G. Macaya, V.I.R., C.E.B., J.S.T., and N.B.F. designed research; L.P. performed research; T.M.T., C.A., X.A., J.B., M.R., G.C., J.G.-M., M.C.L., G. Montoya, C.P.M., I.A., D.G.F., B.S., L.-W.K., K.G., K.C., and J.M. contributed new reagents/analytic tools; C.A., X.A., J.B., M.R., G.C., M.C.L., and C.P.M. interviewed patients and managed clinical databases; J.G.-M. and G. Montoya interviewed patients and collected clinical data; I.A. managed databases and reviewed and performed data quality control; T.M.T., D.G.F., B.S., L.-W.K., K.G., and K.C. reviewed files and performed data quality control; J.M. collected clinical data; L.P., S.K.S., S.C.F., L.N., R.M.C., C.S., J.S.T., and N.B.F. analyzed data; and L.P., S.K.S., C.S., and N.B.F. wrote the paper.

  • Reviewers: M.B., University of Pennsylvania; K.R.M., National Institutes of Health; and E.J.M.M., Stanford University School of Medicine.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1513525113/-/DCSupplemental.

Freely available online through the PNAS open access option.

http://www.pnas.org/preview_site/misc/userlicense.xhtml
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Genetics of circadian rhythms and bipolar disorder
Lucia Pagani, Patricia A. St. Clair, Terri M. Teshiba, Susan K. Service, Scott C. Fears, Carmen Araya, Xinia Araya, Julio Bejarano, Margarita Ramirez, Gabriel Castrillón, Juliana Gomez-Makhinson, Maria C. Lopez, Gabriel Montoya, Claudia P. Montoya, Ileana Aldana, Linda Navarro, Daniel G. Freimer, Brian Safaie, Lap-Woon Keung, Kiefer Greenspan, Katty Chou, Javier I. Escobar, Jorge Ospina-Duque, Barbara Kremeyer, Andres Ruiz-Linares, Rita M. Cantor, Carlos Lopez-Jaramillo, Gabriel Macaya, Julio Molina, Victor I. Reus, Chiara Sabatti, Carrie E. Bearden, Joseph S. Takahashi, Nelson B. Freimer
Proceedings of the National Academy of Sciences Dec 2015, 201513525; DOI: 10.1073/pnas.1513525113

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Genetics of circadian rhythms and bipolar disorder
Lucia Pagani, Patricia A. St. Clair, Terri M. Teshiba, Susan K. Service, Scott C. Fears, Carmen Araya, Xinia Araya, Julio Bejarano, Margarita Ramirez, Gabriel Castrillón, Juliana Gomez-Makhinson, Maria C. Lopez, Gabriel Montoya, Claudia P. Montoya, Ileana Aldana, Linda Navarro, Daniel G. Freimer, Brian Safaie, Lap-Woon Keung, Kiefer Greenspan, Katty Chou, Javier I. Escobar, Jorge Ospina-Duque, Barbara Kremeyer, Andres Ruiz-Linares, Rita M. Cantor, Carlos Lopez-Jaramillo, Gabriel Macaya, Julio Molina, Victor I. Reus, Chiara Sabatti, Carrie E. Bearden, Joseph S. Takahashi, Nelson B. Freimer
Proceedings of the National Academy of Sciences Dec 2015, 201513525; DOI: 10.1073/pnas.1513525113
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