Abnormal structural and functional connectivity (interaction between brain regions) is central to the pathophysiology of psychotic illnesses like schizophrenia and psychotic bipolar disorder. Modern neuroimaging techniques and analytic strategies provide an unprecedented capacity to more fully characterize the functional and structural psychotic disconnectivity. Individuals with psychotic illness and their unaffected relatives have abnormal connectivity, suggesting that at least a portion of psychotic disconnectivity is associated with genetic predisposition for the diseases. Imaging-based connectivity endophenotypes are ideally suited to aid the functional characterization of putative risk genes, allowing us to move beyond a genotype-phenotype association to delineating mechanisms that give rise to psychotic illnesses. Recently, large-scale exome sequencing in individuals of European ancestry provided the strongest evidence to date for specific genetic variants that increase risk for psychosis. These primarily rare mutations were spread across gene networks involved in neuronal processes, including calcium channels and postsynaptic signaling. Our goals are to replicate these promising genetic findings in a different ethnic group, African-Americans, and determine whether and how these gene sets impact psychotic disconnectivity. African-Americans, an underserved population, have ~32% more highly deleterious non-synonymous rare variants in these networks than individuals of European ancestry, improving our power to detect rare variants.
Our aims are to: (1) use modern MRI acquisition and analysis techniques based on the Human Connectome Project to document psychotic disconnectivity in 750 African Americans (375 with a psychotic disorder and 375 demographically matched comparison subjects). We will test hypotheses that diagnostic and dimensional indices of psychosis are associated with reduced global functional connectivity but intact global structural connectivity, combined with aberrant connectivity between specific regions or tracts; (2) conduct whole exome sequencing (WES) to test the influence of rare non-synonymous variants from genes in previously identified gene sets on psychosis risk using a network-centered analysis strategy. We will test hypotheses that the voltage-gated calcium ion channel, and the ARC-associated scaffold protein and the NMDAR postsynaptic signaling complexes influence diagnostic and dimensional indices of psychosis; and (3) apply this same network-centric test to determine if gene sets implicated in illness risk also influence functional and structural psychotic disconnectivity. Linking these genetic pathways to psychotic disconnectivity will provide mechanistic insights into the genomic influences on psychotic illness. Our collaborative application includes sites at Yale/Hartford Hospital (DC Glahn PI), Stanford (RA Poldrack PI) and Texas Biomedical Research Institute (J Blangero PI). Our results should bolster our understanding of the genetic architecture of psychotic illness and provide important clues for traversing the chasm between identified genetic networks and the behaviorally defined disorder.

Public Health Relevance

Structural and functional brain disconnectivity is a hallmark of psychotic disorders, primarily schizophrenia and bipolar disorders. By examining gene networks previously associated with psychosis risk, our study will provide novel insights into the biology o psychotic illness, improving the potential for intervention and treatment. The study will focus on African Americans, a group that has traditionally been understudied in psychiatric genetics and neuroscience.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH106324-03
Application #
9187495
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Gitik, Miri
Project Start
2014-12-10
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
$819,048
Indirect Cost
$59,528
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mathias, Samuel R; Knowles, Emma E M; Barrett, Jennifer et al. (2018) Deficits in visual working-memory capacity and general cognition in African Americans with psychosis. Schizophr Res 193:100-106
Knowles, Emma E M; Mathias, Samuel R; Pearlson, Godfrey D et al. (2018) Clinical correlates of subsyndromal depression in African American individuals with psychosis: The relationship with positive symptoms and comorbid substance dependence. Schizophr Res :
Mathias, Samuel R; Knowles, Emma E M; Barrett, Jennifer et al. (2017) The Processing-Speed Impairment in Psychosis Is More Than Just Accelerated Aging. Schizophr Bull 43:814-823
Owens, Emily M; Bachman, Peter; Glahn, David C et al. (2016) Electrophysiological Endophenotypes for Schizophrenia. Harv Rev Psychiatry 24:129-47