title: Insights into psychosis risk from leukocyte microRNA expression.
abstract: Dysregulation of immune system functions has been implicated in schizophrenia, suggesting that immune cells may be involved in the development of the disorder. With the goal of a biomarker assay for psychosis risk, we performed small RNA sequencing on RNA isolated from circulating immune cells. We compared baseline microRNA (miRNA) expression for persons who were unaffected (n=27) or who, over a subsequent 2-year period, were at clinical high risk but did not progress to psychosis (n=37), or were at high risk and did progress to psychosis (n=30). A greedy algorithm process led to selection of five miRNAs that when summed with +1 weights distinguished progressed from nonprogressed subjects with an area under the receiver operating characteristic curve of 0.86. Of the five, miR-941 is human-specific with incompletely understood functions, but the other four are prominent in multiple immune system pathways. Three of those four are downregulated in progressed vs. nonprogressed subjects (with weight -1 in a classifier function that increases with risk); all three have also been independently reported as downregulated in monocytes from schizophrenia patients vs. unaffected subjects. Importantly, these findings passed stringent randomization tests that minimized the risk of conclusions arising by chance. Regarding miRNA-miRNA correlations over the three groups, progressed subjects were found to have much weaker miRNA orchestration than nonprogressed or unaffected subjects. If independently verified, the leukocytic miRNA biomarker assay might improve accuracy of psychosis high-risk assessments and eventually help rationalize preventative intervention decisions.
authors.affiliation: Renaissance Computing Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Jeffries
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: D O
authors.initials: DO
authors.lastname: Perkins
authors.affiliation: Center for Behavioral Genomics, Department of Psychiatry, and the Institute of Genomic Medicine, University of California, San Diego, San Diego, CA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Chandler
authors.affiliation: Division of Biological Sciences, University of California, San Diego, San Diego, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Stark
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Yeo
authors.affiliation: Hotchkiss Brain Institute, Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Addington
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Bearden
authors.affiliation: Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Cadenhead
authors.affiliation: Departments of Psychology and Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Cannon
authors.affiliation: Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Cornblatt
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Mathalon
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: McGlashan
authors.affiliation: Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston, MA, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychology, Emory University, Atlanta, GA, USA.|Department of Psychiatry, Emory University, Atlanta, GA, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: Walker
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Woods
authors.affiliation: Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Glatt
authors.affiliation: Center for Behavioral Genomics, Department of Psychiatry, and the Institute of Genomic Medicine, University of California, San Diego, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tsuang
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D055633:Immune System Phenomena / Q000235:genetics; D007962:Leukocytes / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000276:immunology; D011618:Psychotic Disorders / Q000235:genetics* / Q000276:immunology*; D018570:Risk Assessment; D012559:Schizophrenia / Q000235:genetics / Q000276:immunology; D012569:Schizotypal Personality Disorder / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: C581560:MIRN941 microRNA, human; D035683:MicroRNAs