title: Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls.
abstract: Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val→Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)-a key enzymatic regulator of cortical dopamine levels-to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val "dose" conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation.
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MA 20892, USA. raznahan@mail.nih.gov
authors.forename: Armin
authors.initials: A
authors.lastname: Raznahan
authors.forename: Deanna
authors.initials: D
authors.lastname: Greenstein
authors.forename: Yohan
authors.initials: Y
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Long
authors.forename: Liv
authors.initials: L
authors.lastname: Clasen
authors.forename: Pete
authors.initials: P
authors.lastname: Gochman
authors.forename: Anjene
authors.initials: A
authors.lastname: Addington
authors.forename: Jay N
authors.initials: JN
authors.lastname: Giedd
authors.forename: Judith L
authors.initials: JL
authors.lastname: Rapoport
authors.forename: Nitin
authors.initials: N
authors.lastname: Gogtay
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000254:growth & development; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D035781:Siblings; D055815:Young Adult
chemical_list: D002394:Catechol O-Methyltransferase