title: The Role of microRNA Expression in Cortical Development During Conversion to Psychosis.
abstract: In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with non-converters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Here we used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N=74). Our cortical thinning classifier included nine microRNAs, p=3.63 × 10-08, R2=0.358, permutation-based p=0.039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (p<0.05, Benjamini-Hochberg corrected). The classifier was also related to proinflammatory cytokine levels in serum (p=0.038). Furthermore, miRNAs that predicted conversion status were found to do so in a manner partially mediated by rate of cortical thinning (point estimate=0.078 (95% CIs: 0.003, 0.168), p=0.03). Many of the miRNAs identified here have been previously implicated in brain development, synaptic plasticity, immune function and/or schizophrenia, showing some convergence across studies and methodologies. Altered intracellular signaling within the immune system may interact with cortical maturation in individuals at high risk for schizophrenia promoting disease onset.
authors.affiliation: Department of Psychology, Yale University, New Haven, CT, USA.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Zheutlin
authors.affiliation: Renaissance Computing Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Clark D
authors.initials: CD
authors.lastname: Jeffries
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Diana O
authors.initials: DO
authors.lastname: Perkins
authors.affiliation: Department of Psychology, Yale University, New Haven, CT, USA.
authors.forename: Yoonho
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Department of Psychology, Yale University, New Haven, CT, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Chekroud
authors.affiliation: Department of Psychiatry, University of Calgary, Alberta, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Addington
authors.affiliation: Department of Psychiatry &Biobehavioral Sciences, University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Bearden
authors.affiliation: Department of Psychiatry, University of California-San Diego, San Diego, CA, USA.
authors.forename: Kristin S
authors.initials: KS
authors.lastname: Cadenhead
authors.affiliation: Department of Psychiatry, Zucker Hillside Hospital, Long Island, NY, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Cornblatt
authors.affiliation: Department of Psychiatry, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Mathalon
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: McGlashan
authors.affiliation: Department of Psychiatry, Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychology, Emory University, Atlanta, GA, USA.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Walker
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Woods
authors.affiliation: Department of Psychiatry, University of California-San Diego, San Diego, CA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tsuang
authors.affiliation: Department of Psychology, Yale University, New Haven, CT, USA.|Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: Tyrone D
authors.initials: TD
authors.lastname: Cannon
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000145:classification / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D011237:Predictive Value of Tests; D062706:Prodromal Symptoms; D011618:Psychotic Disorders / Q000473:pathology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D035683:MicroRNAs