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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085953-05
Application #
8586557
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Friedman-Hill, Stacia
Project Start
2009-12-14
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$414,098
Indirect Cost
$127,324
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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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
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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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