COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome

Biol Psychiatry. 2005 Jul 1;58(1):23-31. doi: 10.1016/j.biopsych.2005.03.020.


Background: Microdeletions at 22q11.2 greatly increase the risk of schizophrenia in early adulthood (relative risk approximately 25-30). We hypothesized that before the onset of schizophrenia, individuals with 22q11DS would manifest specific cognitive and neurophysiological anomalies (endophenotypes) in common with individuals at high risk for schizophrenia in the general population. We further predicted that the catechol-O-methyltransferase Val(108/158)Met polymorphism, located within the deleted chromosomal segment, would modify the severity of endophenotypic features.

Methods: 22q11DS adolescents and young adults (aged 13-21) were compared with age- and IQ-matched control subjects on measures that are associated with risk of idiopathic schizophrenia.

Results: 22q11DS subjects displayed poorer verbal working memory and expressive language performance than control subjects. Auditory mismatch negativity (MMN) event-related potentials were reduced at frontal electrodes but were intact at temporal sites. Presence of the COMT(108/158)Met allele on the single intact chromosome 22 was associated with more marked MMN amplitude reduction and poorer neuropsychological performance. Neither COMT Val(108/158)Met allele influenced psychiatric symptoms.

Conclusions: 22q11DS is associated with neurodevelopmental characteristics that are similar to idiopathic schizophrenia. The COMT Val(108/158)Met polymorphism modifies the severity of endophenotypes for schizophrenia, indicating that impaired catecholamine regulation contributes to neuropsychiatric risk in 22q11DS.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Adolescent
  • Adult
  • Catechol O-Methyltransferase / genetics*
  • Child
  • Chromosomes, Human, Pair 22 / genetics*
  • Cognition Disorders / diagnosis
  • Cognition Disorders / genetics*
  • Electroencephalography / statistics & numerical data
  • Evoked Potentials, Auditory / genetics
  • Evoked Potentials, Auditory / physiology*
  • Female
  • Frontal Lobe / physiology*
  • Gene Deletion*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Methionine / genetics
  • Neuropsychological Tests
  • Phenotype
  • Risk Factors
  • Schizophrenia / genetics*
  • Temporal Lobe / physiology
  • Valine / genetics


  • Methionine
  • Catechol O-Methyltransferase
  • Valine