Schizophrenia and other psychotic disorders are highly disabling conditions with poorly understood pathophysiology. One of the central challenges in elucidating mechanisms of psychosis is its remarkable genetic and phenotypic heterogeneity. Taking a `genetics first' approach (i.e., ascertaining patients based on a known, homogeneous genetic etiology) may allow us to overcome the barriers posed by this complexity. 22q11.2 deletion syndrome (Velocardiofacial/DiGeorge syndrome; 22q11DS) is a particularly compelling model, as it represents the greatest known genetic risk factor for psychosis identified to date. As the deletion can be detected very early in development, it offers an extraordinary opportunity for prospective investigation of early biomarkers of psychosis, long before disease-related processes begin to unfold. In the current funding cycle we have elucidated key points of convergence between disturbances in cognition, neural circuitry and gene expression relevant to psychosis in this genetic risk model and in idiopathic psychosis. In this competitive renewal application we plan to continue to prospectively follow a large cohort of youth with 22q11DS (n=90) through the highest risk period for illness onset, and demographically comparable typically developing controls (n=45), in order to establish whether common mechanisms contribute to psychotic symptomatology in 22q11DS and in idiopathic psychosis. Our primary goals (building on our findings from the original funding period) are to elucidate biological pathways and brain biomarkers which may represent convergent mechanisms for disease evolution. Given new discoveries in clinical high risk populations implicating inflammatory and neurohormonal processes in brain changes associated with the development of psychosis, we have added novel measures to assess these domains. In particular, our aims are to: 1) Investigate baseline and progressive abnormalities in structural and functional brain biomarkers, with the prediction that changes in temporal gray matter and thalamo-cortical functional connectivity will predict worsening cognition, social function and increased psychotic symptoms over time; 2) Determine the role of inflammatory mechanisms and stress sensitivity in the evolution of psychotic symptoms, using assays of both peripheral and neural inflammation [i.e., a novel free water diffusion imaging paradigm which is strongly correlated with positron emission tomography (PET) indices of activated microglia] and cortisol at each timepoint; 3) Determine biological pathways associated with psychosis-relevant phenotypes, by investigating upstream regulatory processes of circulating inflammatory markers; and 4) Given the recent discovery that 22q11.2 duplications may be protective against schizophrenia, we will prospectively follow 30 patients with gain of function mutations in the identical locus in order to investigate gene dosage effects on neurobehavioral phenotypes. This work will advance understanding of the genetic and developmental mechanisms by which 22q11.2 haploinsufficiency disrupts brain structure and function and ultimately contributes to disease pathogenesis.

Public Health Relevance

Chromosomal deletions at 22q11.2 represent the highest known genetic risk factor for the development of psychotic illness. Here we will prospectively study the links between gene expression, brain structure and function, and neurobehavioral outcomes in youth with 22q11.2 deletions, in order to advance our understanding of the mechanisms underlying the development of psychotic symptoms during the critical adolescent period in this biologically vulnerable population. These findings will also shed light on genetic influences that can disrupt brain development and, in turn, influence psychosis risk in the broader population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH085953-06A1
Application #
9177247
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
2021-05-31
Budget Start
2016-09-06
Budget End
2017-05-31
Support Year
6
Fiscal Year
2016
Total Cost
$714,789
Indirect Cost
$214,179
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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
Oestreich, Lena K L; Lyall, Amanda E; Pasternak, Ofer et al. (2017) Characterizing white matter changes in chronic schizophrenia: A free-water imaging multi-site study. Schizophr Res 189:153-161
Schreiner, Matthew; Forsyth, Jennifer K; Karlsgodt, Katherine H et al. (2017) Intrinsic Connectivity Network-Based Classification and Detection of Psychotic Symptoms in Youth With 22q11.2 Deletions. Cereb Cortex 27:3294-3306
Jalbrzikowski, Maria; Ahmed, Khwaja Hamzah; Patel, Arati et al. (2017) Categorical versus dimensional approaches to autism-associated intermediate phenotypes in 22q11.2 microdeletion syndrome. Biol Psychiatry Cogn Neurosci Neuroimaging 2:53-65
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

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