Introduction: This application has two main objectives: (1) facilitate Dr. Monica E. Calkins' continued transition to independent investigator; (2) undertake a longitudinal investigation of risk factors (endophenotypes) in youths judged at high risk of developing psychosis. Background: Schizophrenia is a severe mental disorder affecting one out of every 100 adults. Yet, genes contributing to schizophrenia risk remain elusive, rendering it impossible to develop programs for early identification and prevention of this tragic disorder. A major obstacle is that the disorder we call schizophrenia is not the best target for the gene search. Instead, we should target simpler characteristics called """"""""endophenotypes"""""""", e.g., abilities like remembering, paying attention, and producing simple eye movements. Research with adult schizophrenia patients and their families indicates that emdophenotypes are associated with schizophrenia and tend to run in families. However, .little work has evaluated them in young people to determine whether they can help us predict, and possibly prevent, the development of schizophrenia. Growing evidence indicates that """"""""prodromal"""""""" symptoms occurring prior to the full-blown illness are associated with a high rate of conversion to schizophrenia. The current application aims to merge endophenotype and prodromal strategies to examine the developmental course and heritability of endophenotypes in youths at-risk for psychosis. Research Project: A battery of psychophysiological and neuropsychological candidate endophenotypes will be prospectively assessed in 60 young (age 14-25) pairs of siblings. Comprehensive baseline diagnostic assessment will allow classification of probands as (a) genetic + clinical risk for schizophrenia (prodromal symptoms + immediate family member with schizophrenia; 20 pair) (b) clinical risk for schizophrenia (prodromal symptoms + no family history; 20 pair) or (c) low-risk for schizophrenia (no prodromal symptoms or family history; 20 pair). Follow-up (1 yr) will inform the developmental course of endophenotypes and relationship to prodromal symptoms. Environment: Training will occur at the University of Pennsylvania under the mentorship of Bruce Turetsky, M.D., and Raquel Gur, M.D., Ph.D. Research Career Development: Through mentored activities and formal coursework, the candidate seeks to (1) develop expertise in the design and analysis of an expanded repertoire of endophenotypes; (2) enhance her knowledge of recruitment, diagnosis and treatment of at-risk adolescents; (3) develop proficiency in longitudinal analysis of developmental data (4) enhance her knowledge of psychiatric genetic and epidemiology methods (5) prepare and submit an R01. Relevance: Detection of candidate endophenotypes in vulnerable individuals could help narrow the search for schizophrenia susceptibility genes by providing evidence that inherited characteristics associated with schizophrenia are seen prior to illness onset, and one day could be used in early identification and intervention. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH079364-02
Application #
7485225
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Churchill, James D
Project Start
2007-08-16
Project End
2012-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$146,243
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kaczkurkin, A N; Moore, T M; Calkins, M E et al. (2018) Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses. Mol Psychiatry 23:1981-1989
Xia, Cedric Huchuan; Ma, Zongming; Ciric, Rastko et al. (2018) Linked dimensions of psychopathology and connectivity in functional brain networks. Nat Commun 9:3003
Calkins, Monica E; Moore, Tyler M; Satterthwaite, Theodore D et al. (2017) Persistence of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort: a prospective two-year follow-up. World Psychiatry 16:62-76
Tang, S X; Moore, T M; Calkins, M E et al. (2017) Emergent, remitted and persistent psychosis-spectrum symptoms in 22q11.2 deletion syndrome. Transl Psychiatry 7:e1180
Jones, Jason D; Scott, J Cobb; Calkins, Monica E et al. (2017) Correspondence between adolescent and informant reports of substance use: Findings from the Philadelphia Neurodevelopmental Cohort. Addict Behav 65:13-18
Jones, Jason D; Calkins, Monica E; Scott, J Cobb et al. (2017) Cannabis Use, Polysubstance Use, and Psychosis Spectrum Symptoms in a Community-Based Sample of U.S. Youth. J Adolesc Health 60:653-659
Scott, J Cobb; Wolf, Daniel H; Calkins, Monica E et al. (2017) Cognitive functioning of adolescent and young adult cannabis users in the Philadelphia Neurodevelopmental Cohort. Psychol Addict Behav 31:423-434
Mekori-Domachevsky, Ehud; Guri, Yael; Yi, James et al. (2017) Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: A two-site study. Schizophr Res 188:42-49
Tang, Sunny X; Moore, Tyler M; Calkins, Monica E et al. (2017) The Psychosis Spectrum in 22q11.2 Deletion Syndrome Is Comparable to That of Nondeleted Youths. Biol Psychiatry 82:17-25
Germine, L; Robinson, E B; Smoller, J W et al. (2016) Association between polygenic risk for schizophrenia, neurocognition and social cognition across development. Transl Psychiatry 6:e924

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