title: Transcriptomic Analysis of Induced Pluripotent Stem Cells Derived from Patients with Bipolar Disorder from an Old Order Amish Pedigree.
abstract: Fibroblasts from patients with Type I bipolar disorder (BPD) and their unaffected siblings were obtained from an Old Order Amish pedigree with a high incidence of BPD and reprogrammed to induced pluripotent stem cells (iPSCs). Established iPSCs were subsequently differentiated into neuroprogenitors (NPs) and then to neurons. Transcriptomic microarray analysis was conducted on RNA samples from iPSCs, NPs and neurons matured in culture for either 2 weeks (termed early neurons, E) or 4 weeks (termed late neurons, L). Global RNA profiling indicated that BPD and control iPSCs differentiated into NPs and neurons at a similar rate, enabling studies of differentially expressed genes in neurons from controls and BPD cases. Significant disease-associated differences in gene expression were observed only in L neurons. Specifically, 328 genes were differentially expressed between BPD and control L neurons including GAD1, glutamate decarboxylase 1 (2.5 fold) and SCN4B, the voltage gated type IV sodium channel beta subunit (-14.6 fold). Quantitative RT-PCR confirmed the up-regulation of GAD1 in BPD compared to control L neurons. Gene Ontology, GeneGo and Ingenuity Pathway Analysis of differentially regulated genes in L neurons suggest that alterations in RNA biosynthesis and metabolism, protein trafficking as well as receptor signaling pathways may play an important role in the pathophysiology of BPD.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Kwi Hye
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Sells Galvin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Dage
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Egeland
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Rosamund C
authors.initials: RC
authors.lastname: Smith
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
authors.forename: Kalpana M
authors.initials: KM
authors.lastname: Merchant
authors.affiliation: Mind and Brain Institute, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
mesh_terms: D000328:Adult; D061365:Amish; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D010375:Pedigree; D059467:Transcriptome; D062585:Voltage-Gated Sodium Channel beta-4 Subunit / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C477263:SCN4B protein, human; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1