title: Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients.
abstract: Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of 'clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3β genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.
authors.affiliation: 1] Psychiatry Service, Veterans Affairs San Diego Healthcare System, University of California, San Diego, CA, USA [2] Department of Psychiatry, University of California, San Diego, CA, USA [3] Center for Chronobiology, University of California, San Diego, CA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: McCarthy
authors.forename: H
authors.initials: H
authors.lastname: Wei
authors.forename: Z
authors.initials: Z
authors.lastname: Marnoy
authors.forename: R M
authors.initials: RM
authors.lastname: Darvish
authors.forename: D L
authors.initials: DL
authors.lastname: McPhie
authors.forename: B M
authors.initials: BM
authors.lastname: Cohen
authors.forename: D K
authors.initials: DK
authors.lastname: Welsh
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics*; D056950:Period Circadian Proteins / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C421902:PER2 protein, human; C512644:PER3 protein, human; D056950:Period Circadian Proteins; C539738:RORA protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3