Author:
Pagani Lucia,St. Clair Patricia A.,Teshiba Terri M.,Service Susan K.,Fears Scott C.,Araya Carmen,Araya Xinia,Bejarano Julio,Ramirez Margarita,Castrillón Gabriel,Gomez-Makhinson Juliana,Lopez Maria C.,Montoya Gabriel,Montoya Claudia P.,Aldana Ileana,Navarro Linda,Freimer Daniel G.,Safaie Brian,Keung Lap-Woon,Greenspan Kiefer,Chou Katty,Escobar Javier I.,Ospina-Duque Jorge,Kremeyer Barbara,Ruiz-Linares Andres,Cantor Rita M.,Lopez-Jaramillo Carlos,Macaya Gabriel,Molina Julio,Reus Victor I.,Sabatti Chiara,Bearden Carrie E.,Takahashi Joseph S.,Freimer Nelson B.
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.
Funder
HHS | NIH | National Institute of Mental Health
HHS | NIH | National Human Genome Research Institute
Howard Hughes Medical Institute
Publisher
Proceedings of the National Academy of Sciences