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 GreenspanKatty 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

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E754-E761
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Feb 9 2016


  • Actigraphy
  • Behavior
  • Bipolar disorder
  • Circadian rhythms
  • Endophenotypes

ASJC Scopus subject areas

  • General


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