Despite intensive search for schizophrenia susceptibility genes, the genetic basis of this devastating mental illness remains elusive. Newly emerging evidence suggests that rare genetic mutations that disrupt neurodevelopmental pathways may play a larger role in the illness than was previously believed. Thus, a complementary strategy that may provide valuable insights into the pathogenesis of schizophrenia is the study of a disorder with known genetic etiology that shares its phenotypic characteristics. The 22q11.2 deletion syndrome (Velocardiofacial/ DiGeorge syndrome;22qDS) is a compelling model, as it represents the most common known genetic risk factor for the development of psychotic illness. Because 22qDS has a known genetic etiology and consistent neurobehavioral phenotype, investigation of this syndrome offers an extraordinary opportunity for narrowing the search among possible neuroanatomic and genetic mechanisms underlying the development of psychotic symptoms in adolescence. Here we propose to conduct 2-year longitudinal investigations (over a 5-year funding period) of a large cohort of children and adolescents with 22qDS and demographically comparable healthy controls. We will apply dimensional measures of psychopathology, neurocognitive assays, and novel brain imaging methods, in order to elucidate risk factors for emergence of psychotic symptoms during adolecence in youth with this syndrome. In particular, we will test the hypotheses that more severe structural brain anomalies at baseline, as well as progressive worsening over time, are predictive of symptom severity in 22qDS, consistent with the theoretical involvement of deviant adolescent neuromaturational processes in psychotic symptom development. These differences will be examined in relation to variability in deletion size and to hemizygous allelic variability in neurodevelopmental genes within the 22q11.2 locus. This work will establish the neural substrates for the neurobehavioral phenotypes seen in 22qDS, and advance our understanding of the genetic and developmental mechanisms by which haploinsufficiency at 22q11.2 compromises brain structure and function.
Chromosomal deletions at 22q11.2 represent the highest known genetic risk factor for development of psychotic illness. Here we will prospectively study the links between genetic variation, brain structure, and behavior in children with 22q11.2 deletions, in order to advance our understanding of the mechanisms underlying the development of psychotic symptoms during adolescence in this syndrome. These findings will also shed light on genetic influences on brain development and psychosis in the broader population.
|Sun, Daqiang; Ching, Christopher R K; Lin, Amy et al. (2018) Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size. Mol Psychiatry :|
|Guo, Tingwei; Diacou, Alexander; Nomaru, Hiroko et al. (2018) Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2. Hum Mol Genet 27:1150-1163|
|Hampton, Joya N; Trotman, Hanan D; Addington, Jean et al. (2018) The relation of atypical antipsychotic use and stress with weight in individuals at clinical high risk for psychosis. Stress Health 34:591-600|
|Bearden, Carrie E; Thompson, Paul M (2017) Emerging Global Initiatives in Neurogenetics: The Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) Consortium. Neuron 94:232-236|
|Lin, Amy; Ching, Christopher R K; Vajdi, Ariana et al. (2017) Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry. J Neurosci 37:6183-6199|
|Bassett, Anne S; Lowther, Chelsea; Merico, Daniele et al. (2017) Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome. Am J Psychiatry 174:1054-1063|
|Bearden, Carrie E; Glahn, David C (2017) Cognitive genomics: Searching for the genetic roots of neuropsychological functioning. Neuropsychology 31:1003-1019|
|Weisman, Omri; Guri, Yael; Gur, Raquel E et al. (2017) Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study. Schizophr Bull 43:1079-1089|
|Guo, Tingwei; Repetto, Gabriela M; McDonald McGinn, Donna M et al. (2017) Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3. Circ Cardiovasc Genet 10:|
|Gur, R E; Bassett, A S; McDonald-McGinn, D M et al. (2017) A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium. Mol Psychiatry 22:1664-1672|
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