Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls.
- Authors
- Raznahan, Armin; Greenstein, Deanna; Lee, Yohan; Long, Robert; Clasen, Liv; Gochman, Pete; Addington, Anjene; Giedd, Jay N; Rapoport, Judith L; Gogtay, Nitin
- Year
- 2011
- Journal
- NeuroImage
- PMID
- 21620981
- DOI
- 10.1016/j.neuroimage.2011.05.032
- PMCID
- PMC3285479
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.
Lateral and medial views of the cortical surface summarizing regions where Val158Met genotype was associated with significant (FDR corrected q < 0.05) difference in the rate of CT loss in Healthy Controls (HCs). Colored regions indicate where HCs show a step-wise reduction in the rate of CT loss for each extra Val allele. The inset plot illustrates this for the left dorsolateral prefrontal cortex.
Regions where the relationship between COMT Val158Met Val allele dose and cortical thickness change is significantly different in healthy controls (HCs) as compared to probands with Childhood Onset Schizophrenia (COS). The inset plot illustrates this interaction for the left dorsolateral prefrontal region, where increased Val dose attenuates cortical thinning on HCs, but accelerates it in probands with COS. Note that by adulthood, COS Val homozygotes have persistent cortical thickness deficits compared to HCs, whereas Met homozygotes do not. All colored regions shown survive False Discovery Rate correction for multiple comparisons at q < 0.05.
Regions where the relationship between COMT Val158Met Val allele dose and cortical thickness change is significantly different in healthy controls (HCs) as compared to the unaffected siblings (SIBs) of probands with schizophrenia. The inset plot illustrates this interaction for the left inferior temporal region, where increased Val dose attenuates cortical thinning on HCs, but accelerates it in SIBs. Note that by adulthood, cortical thickness trajectories have converged between HC and SIB groups—regardless of Val dose. All colored regions shown survive False Discovery Rate correction for multiple comparisons at q < 0.05.
| Name | Type |
|---|---|
| abnormal brain anatomical change local | phenotype |
| activational efficiency local | phenotype |
| adolescent cortical thickness loss local | phenotype |
| anterior cingulate cortex | anatomy |
| bilateral cingulate local | anatomy |
| bilateral inferior frontal gyrus local | anatomy |
| brain | anatomy |
| brain development | phenotype |
| cerebral hemispheres | anatomy |
| cerebrospinal fluid | drug |
| childhood-onset schizophrenia local | cohort |
| childhood-onset schizophrenia local | phenotype |
| Childhood-onset schizophrenia local | cohort |
| Childhood-onset schizophrenia local | phenotype |
| children with schizophrenia local | cohort |
| cingulate cortex | anatomy |
| Clinical Group local | cohort |
| COMT | gene |
| COMT Val158 | gene |
| COMT Val158Met | gene |
| cortex | anatomy |
| cortical D1 density local | phenotype |
| cortical DA signaling local | phenotype |
| cortical dysmaturation local | phenotype |
| cortical folding patterns local | phenotype |
| cortical function | phenotype |
| cortical hypodopaminergia local | phenotype |
| cortical maturation local | phenotype |
| Cortical maturation local | phenotype |
| Cortical structure local | phenotype |
| cortical surface | anatomy |
| cortical thickness | phenotype |
| cortical thickness change local | anatomy |
| Cortical thickness change local | phenotype |
| cortical thickness deficits local | phenotype |
| Cortical thickness maturation local | phenotype |
| COS local | cohort |
| COS local | phenotype |
| COS probands local | cohort |
| CSF local | anatomy |
| CT | phenotype |
| CT deficits local | phenotype |
| dlPFC | anatomy |
| dlPFC cortical thickness deficit local | phenotype |
| dopamine | drug |
| dopamine dysregulation local | phenotype |
| dopamine-modifying drugs local | drug |
| Dopaminergic dysregulation local | phenotype |
| Dopamine signaling genetic variants local | variant |
| dorsolateral prefrontal cortex | anatomy |
| DRD2 | gene |
| executive function | phenotype |
| exploitative behavior local | phenotype |
| exploratory behavior | phenotype |
| families | cohort |
| Family history cohort local | cohort |
| Fronto-temporal cortex local | anatomy |
| fronto-temporal gray matter deficit local | phenotype |
| Fronto-temporal sub-regions local | anatomy |
| full-scale IQ | phenotype |
| functional abnormalities | phenotype |
| functional interconnectivity local | phenotype |
| Genetic liability for schizophrenia local | phenotype |
| genetic risk | cohort |
| genetic variant impacting dopamine signaling local | variant |
| gray matter | anatomy |
| gray/pial surface local | anatomy |
| gray/white boundary | anatomy |
| gyrification local | phenotype |
| HC | cohort |
| hCS | cohort |
| healthy brain development local | phenotype |
| healthy controls | cohort |
| higher associative cortices local | anatomy |
| high-risk offspring | cohort |
| inferior temporal cortex local | anatomy |
| intellectual ability local | phenotype |
| inter-neuron differentiation local | phenotype |
| language | phenotype |
| lateral prefrontal cortex | anatomy |
| Lateral temporal region local | anatomy |
| lateral temporal regions local | anatomy |
| left dlPFC | anatomy |
| left intraparietal sulcus local | anatomy |
| lymphoblastoid cell lines | cohort |
| mean age | phenotype |
| medPFC local | anatomy |
| meso-cortical circuit local | anatomy |
| meso-limbic circuit local | anatomy |
| meso-striatal circuit local | anatomy |
| Met allele local | variant |
| MetMet genotype local | variant |
| Middle cingulate cortex local | anatomy |
| MNI-ICBM152 Stereotaxic Space local | anatomy |
| neurogenesis | phenotype |
| neuronal differentiation | phenotype |
| non-psychotic siblings local | cohort |
| Non-psychotic siblings local | cohort |
| non-white groups local | phenotype |
| oscillatory activity | phenotype |
| Parietal associative cortices local | anatomy |
| parietal cortex | anatomy |
| Performance IQ | phenotype |
| persistent cortical thickness deficits local | phenotype |
| persistent fronto-temporal gray matter deficit local | phenotype |
| PFC | anatomy |
| PFC hypodopaminergia local | phenotype |
| prefrontal cortex | anatomy |
| probands | cohort |
| prodromal symptoms | phenotype |
| psychosis | phenotype |
| Race distribution local | phenotype |
| race/ethnicity | phenotype |
| reduced PFC functioning local | phenotype |
| rs4680 | variant |
| schizophrenia | phenotype |
| sex | phenotype |
| SIB local | cohort |
| siblings | cohort |
| signal-to-noise ratio | phenotype |
| structural cortical deficits local | phenotype |
| Structural maturation abnormalities local | phenotype |
| structural MRI | drug |
| STS local | anatomy |
| study cohort | cohort |
| subjects | cohort |
| superior parietal cortex | anatomy |
| superior temporal cortex local | anatomy |
| surface area | phenotype |
| temporal cortex | anatomy |
| Twin cohort | cohort |
| typical development | phenotype |
| unaffected SIBs local | cohort |
| Val158 allele | gene |
| Val158Met | gene |
| Val158Met genotype local | variant |
| Val allele | gene |
| Val allele dosage local | variant |
| ValMet genotype local | variant |
| Valproic acid | drug |
| ValVal genotype local | variant |
| Velocardiofacial syndrome | phenotype |
| Verbal IQ local | phenotype |
| vocabulary | phenotype |
| white matter | anatomy |
| working memory | phenotype |
| β4 coefficient local | variant |
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