Recent studies provide considerable evidence that schizophrenia (SZ) and psychotic bipolar disorder (BP) may share overlapping etiologic determinants. Identifying disease-related genetic effects is a major focus in SZ and BP research, with enormous implications for diagnosis and treatment for these two disorders. Efforts have been multifaceted, with the ultimate goal of describing causal paths from specific genetic variants, to changes in neuronal functioning, to altered brain anatomy, to behavioral and functional impairments. Parallel efforts have identified and refined several alternative endophenotypes that are stable, heritable, have (partly) known biological substrates, and are associated with psychosis liability. Although many such endophenotypes have been individually studied in SZ, and to a lesser extent in BP, no study has comprehensively assessed a broad panel of these markers in the two disorders with parallel recruitment, and the extent to which they mark independent aspects of psychosis risk, or their overlap in the two disorders. This line of investigation will potentially impact our conceptualization of psychotic disorders, help us make critical strides to identify the pathophysiology of psychosis, and guide development of new specific treatments targeting particular deficits. The overall goal of the proposed research is to examine a broad panel of putative endophenotypes in affected individuals with schizophrenia and bipolar and their unaffected relatives in order to: 1) characterize the degree of familial phenotypic overlap between SZ and psychotic BP;2) identify patterns of endophenotypes unique to the two disorders, and 3) contrast the heritability of endophenotypes across the disorders. To achieve these goals, we will recruit 500 SZ and 500 BP I (with psychosis) probands, ~1700-2000 1st degree relatives of these probands, and 500 unrelated non-psychiatric controls from five centers. We will obtain measures of neurophysiology (e.g., eye tracking, P50 gating, PPI, and P300), neurocognition (e.g., attention/vigilance, episodic and working memory), and brain structure (e.g., volumes of gray and white matter in specified brain regions). We will collect blood for future genetic studies. We will assess the degree of familial aggregation of endophenotypes in SZ and BP relatives. Establishing similarities and differences in the endophenotypic signatures within SZ and BP families will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry. This research will be conducted by 5 experienced research groups, with a long history of close and productive collaboration. Public Health Relevance: This multisite project will identify endophenotypes (or liability markers) that are shared and different in schizophrenia and bipolar disorder. Findings from these studies will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH077851-04S1
Application #
8426462
Study Section
Special Emphasis Panel (ZRG1-HOP-V (60))
Program Officer
Rumsey, Judith M
Project Start
2007-09-29
Project End
2013-05-31
Budget Start
2012-05-16
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$175,255
Indirect Cost
$64,916
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Rubin, Leah H; Connelly, Jessica J; Reilly, James L et al. (2016) Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders. Biol Psychiatry Cogn Neurosci Neuroimaging 1:141-151
Padmanabhan, Jaya L; Nanda, Pranav; Tandon, Neeraj et al. (2016) Polygenic risk for type 2 diabetes mellitus among individuals with psychosis and their relatives. J Psychiatr Res 77:52-8
Nanda, Pranav; Tandon, Neeraj; Mathew, Ian T et al. (2016) Impulsivity across the psychosis spectrum: Correlates of cortical volume, suicidal history, and social and global function. Schizophr Res 170:80-6
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Mothi, Suraj Sarvode; Tandon, Neeraj; Padmanabhan, Jaya et al. (2015) Increased cardiometabolic dysfunction in first-degree relatives of patients with psychotic disorders. Schizophr Res 165:103-7
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Lui, S; Yao, L; Xiao, Y et al. (2015) Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives. Psychol Med 45:97-108
Meda, Shashwath A; Wang, Zheng; Ivleva, Elena I et al. (2015) Frequency-Specific Neural Signatures of Spontaneous Low-Frequency Resting State Fluctuations in Psychosis: Evidence From Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Consortium. Schizophr Bull 41:1336-48

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