title: Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: a preliminary analysis.
abstract: First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. Although preliminary, our results suggest the utility of peripheral measures in the identification of biomarkers of risk in high-risk populations and further emphasize the potential role of stress and DNA methylation in the risk for BD in youth.
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Fries
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.|Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.|Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.|Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Quevedo
authors.affiliation: Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Zeni
authors.affiliation: Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
authors.forename: I F
authors.initials: IF
authors.lastname: Kazimi
authors.affiliation: Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zunta-Soares
authors.affiliation: Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Spiker
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Bowden
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.|Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.|Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Walss-Bass
authors.affiliation: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.|Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Soares
mesh_terms: D000293:Adolescent; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D016241:Child of Impaired Parents; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D012306:Risk; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics
chemical_list: D018840:HSP70 Heat-Shock Proteins; C543454:HSPA1L protein, human; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D012333:RNA, Messenger; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors