COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome

Gothelf, Doron; Eliez, Stéphan; Thompson, Tracy; Hinard, Christine; Penniman, Lauren; Feinstein, Carl; Kwon, Hower; Jin, Shuting; Jo, Booil; Antonarakis, Stylianos E.; Morris, Michael A.; Reiss, Allan L.

doi:10.1038/nn1572

Cited by 294 publications

(296 citation statements)

References 15 publications

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“…The time 1 (T1) sample, collected between 1998 and 2000, included 29 children with 22q11.2DS and 29 typically developing (TD) controls [nineteen 22q11.2DS subjects and no controls participated in a previous study by our group that reported on prefrontal imaging data (Gothelf et al, 2005)]. Prospective recruitment was performed through the Northern California Velocardiofacial Association and by advertising on our web site (cibsr.stanford.edu).…”

Section: Participantsmentioning

confidence: 99%

“…Most striking, up to one third of subjects with 22q11.2DS develop schizophrenia-like psychotic disorders by early adulthood. This makes 22q11.2DS the most common identifiable genetic risk factor for schizophrenia (Gothelf et al, 2005;Murphy et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, we focused on identifying neuroanatomical markers for the evolution of psychotic disorders and for the decline in VIQ scores that were identified in a previous study of this cohort (Gothelf et al, 2005). We hypothesized that changes in the above mentioned candidate brain regions would be more robust in those 22q11.2DS individuals who developed psychotic disorders compared to those who remained nonpsychotic.…”

Section: Introductionmentioning

confidence: 99%

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Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

Gothelf

Penniman

et al. 2007

Schizophrenia Research

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The 22q11.2 deletion syndrome (22q11.2DS) is associated with very high rates of schizophrenialike psychosis and cognitive deficits. Here we report the results of the first longitudinal study assessing brain development in individuals with 22q11.2DS. Twenty-nine children with 22q11.2DS and 29 age and gender matched controls were first assessed during childhood or early adolescence; Nineteen subjects with 22q11.2DS and 18 controls underwent follow-up during late adolescenceearly adulthood. The 22q11.2DS subjects showed greater longitudinal increase in cranial and cerebellar white matter, superior temporal gyrus, and caudate nucleus volumes. They also had a more robust decrease in amygdala volume. Verbal IQ (VIQ) scores of the 22q11.2DS group that developed psychotic disorders declined significantly between assessments. Decline in VIQ in 22q11.2DS was associated with more robust reduction of left cortical grey matter volume. No volumetric differences were detected between psychotic and nonpsychotic subjects with 22q11.2DS. Brain maturation associated with verbal cognitive development in 22q11.2DS varies from that observed in healthy controls. Further longitudinal studies are likely to elucidate brain developmental trajectories in 22q11.2DS and their association to psychotic disorders and cognitive deficits in this population.

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Section: Participantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

Gothelf

Penniman

et al. 2007

Schizophrenia Research

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“…COMT may influence cognitive functioning and psychosis [142][143][144]. Epistasis may also occur between COMT and PRODH, and is likely to affect behavior [139].…”

Section: Q112mentioning

confidence: 99%

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

et al. 2015

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Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

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“…In the only longitudinal neuroimaging study of 22q11.2DS to date, Gothelf et al [2005] found that the COMT low-activity (Met) allele was associated with decline in prefrontal cortical volume and cognition, and with development of psychotic symptoms during adolescence. These intriguing findings highlight the importance of investigating the evolution of psychotic symptoms in relation to genes and neuroanatomy over time in this syndrome.…”

Section: Brain Mapping In Rare Neurogenetic Disorders Associated Withmentioning

confidence: 99%

Cortical mapping of genotype–phenotype relationships in schizophrenia

Bearden

Erp

Thompson

et al. 2007

Human Brain Mapping

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Although schizophrenia is highly heritable, the search for susceptibility genes has been challenging. The "endophenotype" approach is an alternative method for measuring phenotypic variation that may make it easier to identify susceptibility genes in the context of complexly inherited traits. Neuroimaging methods in particular offer a powerful way to bridge the neurobiology of genes and behavior. Such investigations may be further empowered by complementary strategies involving chromosomal abnormalities associated with schizophrenia, which can help to localize causative genes and better understand the genetic complexity of the illness. Here, we illustrate our use of these convergent approaches, with a focus on neuroimaging studies using novel computational brain mapping algorithms, to investigate genetic influences on brain structure in the development of psychosis. These studies provide compelling evidence that specific genetic loci suspected to predispose to schizophrenia may affect quantitative variation in neural indicators underlying the neurobehavioral phenotype, and illustrate how geneticneuroimaging paradigms can improve our understanding of the pathogenesis of this highly disabling mental illness.

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COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome

Cited by 294 publications

References 15 publications

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

Cortical mapping of genotype–phenotype relationships in schizophrenia

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