Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
Image credit: Shutterstock/Dmitry Naumov.
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)
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.
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.xhtmlGenetics of circadian rhythms and bipolar disorder
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Recent experiments and simulations are starting to answer some fundamental questions about how life came to be.
Image credit: Shutterstock/Radoslaw Lecyk.
Archaeologists have long tried to define the transition between the two time periods.
Image credit: Ceri Shipton.
Jonathon Yuly, David Beratan, and Peng Zhang investigate how electron bifurcation reactions work.
A study finds that giant pandas roll in horse manure to increase their cold tolerance.
Image credit: Fuwen Wei.
See related content: