COMT Val108/158Met Modifies Mismatch Negativity and Cognitive Function in 22q11 Deletion Syndrome

Background Microdeletions at 22q11.2 greatly increase the risk of schizophrenia in early adulthood (relative risk ≈ 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 Val108/158Met 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 COMT108/158Met allele on the single intact chromosome 22 was associated with more marked MMN amplitude reduction and poorer neuropsychological performance. Neither COMT Val108/158Met allele influenced psychiatric symptoms. Conclusions 22q11DS is associated with neurodevelopmental characteristics that are similar to idiopathic schizophrenia. The COMT Val108/158Met polymorphism modifies the severity of endophenotypes for schizophrenia, indicating that impaired catecholamine regulation contributes to neuropsychiatric risk in 22q11DS.