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Temperament & Character Account For Brain Functional Connectivity At Rest: A Diathesis-Stress Model Of Functional Dysregulation In Psychosis, Igor Zwir, Javier Arnedo, Alberto Mesa, Coral Del Val, Gabriel A. De Erausquin, C. Robert Cloninger

School of Medicine Publications and Presentations

The human brain’s resting-state functional connectivity (rsFC) provides stable trait-like measures of differences in the perceptual, cognitive, emotional, and social functioning of individuals. The rsFC of the prefrontal cortex is hypothesized to mediate a person’s rational self-government, as is also measured by personality, so we tested whether its connectivity networks account for vulnerability to psychosis and related personality configurations. Young adults were recruited as outpatients or controls from the same communities around psychiatric clinics. Healthy controls (n = 30) and clinically stable outpatients with bipolar disorder (n = 35) or schizophrenia (n = 27) were diagnosed by …

Genome-Wide Association Studies Of Schizophrenia And Bipolar Disorder In A Diverse Cohort Of Us Veterans, Tim B. Bigdeli, Ayman H. Fanous, Yuli Li, Nallakkandi Rajeevan, Frederick Sayward, Giulio Genovese, Rishab Gupta, Krishnan Radhakrishnan, Anil K. Malhotra, Michael A. Escamilla

School of Medicine Publications and Presentations

Background: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572.

Methods: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the …

A White Matter Connection Of Schizophrenia And Alzheimer’S Disease, Peter Kochunov, Artemis Zavaliangos-Petropulu, Neda Jahanshad, Paul M. Thompson, Meghann C. Ryan, Joshua Chiappelli, Shuo Chen, Xiaoming Du, Kathryn Hatch, Bhim Adhikari, Joanne E. Curran, John Blangero

School of Medicine Publications and Presentations

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer’s disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter “regional vulnerability index” (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent …

Cognitive Impairment From Early To Middle Adulthood In Patients With Affective And Nonaffective Psychotic Disorders, Josephine Mollon, Samuel R. Mathias, Emma Knowles, Amanda Rodrigue, Marinka M. G. Koenis, Godfrey D. Pearlson, Abraham Reichenberg, Jennifer Barrett, Dominique Denbow, Katrina Aberizk, Molly Zatony, Russell A. Poldrack, John Blangero, David C. Glahn

School of Medicine Publications and Presentations

Background.—Cognitive impairment is a core feature of psychotic disorders, but the profile of impairment across adulthood, particularly in African-American populations, remains unclear.

Methods.—Using cross-sectional data from a case–control study of African-American adults with affective (n = 59) and nonaffective (n = 68) psychotic disorders, we examined cognitive functioning between early and middle adulthood (ages 20–60) on measures of general cognitive ability, language, abstract reasoning, processing speed, executive function, verbal memory, and working memory.

Results.—Both affective and nonaffective psychosis patients showed substantial and widespread cognitive impairments. However, comparison of cognitive functioning between controls and psychosis groups throughout early …

Role Of Naltrexone In Improving Compulsive Drinking In Psychogenic Polydipsia, Sukaina Rizvi, Jeffery Gold, Ali M. Khan

School of Medicine Publications and Presentations

Psychogenic polydipsia or self-induced water intoxication is a potentially lethal condition seen in many chronic psychiatric patients. This is a literature review based on therapeutic significance of Naltrexone in improving compulsive water drinking behavior in chronic psychiatrically ill patients with psychogenic polydipsia. Naltrexone is an opioid antagonist approved by FDA for alcohol dependence. Extensive literature search provides a line of evidence that suggests correlation of opioid receptor with compulsive water ingestion in animals. However, there is limited data regarding clinical utility of naltrexone in improving psychogenic polydipsia in human species. This review highlights the necessity for further research and trials …

Dopamine Perturbation Of Gene Co-Expression Networks Reveals Differential Response In Schizophrenia For Translational Machinery, Mark Z. Kos, Jubao Duan, Alan R. Sanders, Lucy Blondell, Eugene I. Drigalenko, Melanie A. Carless, Pablo V. Gejman, Harald H. H. Goring

School of Medicine Publications and Presentations

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). …

Efficacy And Safety Of Varenicline For Smoking Cessation In Schizophrenia: A Meta-Analysis, Saeed Ahmed, Sanya Virani, Vijaya P. Kotapati, Ramya Bachu, Mahwish Adnan, Ali M. Khan

School of Medicine Publications and Presentations

Objective: Smoking represents a major public health problem among patients with schizophrenia. To this end, some studies have investigated the efficacy of varenicline for facilitating smoking cessation in schizophrenia patients. The present review seeks to synthesize the results of these studies as well as document the reported side effects of using this medication.

Methods: An electronic search was performed using five major databases: PubMed, Scopus, EMBASE, Web of Science, and Cochrane Library. Included in the current analysis were randomized clinical trials (RCTs) that have investigated the effect of varenicline in promoting smoking cessation in patients with schizophrenia. Risk of …

Schizophrenia In Digeorge Syndrome: A Unique Case Report, Sukaina Rizvi, Ali M. Khan, Hina Saeed, Akeem M. Aribara, Alexis Carrington, Alexa Griffiths, Abdul Mohit

School of Medicine Publications and Presentations

Herein we present the unique case of a 21-year-old African American woman who presented with psychotic features and the incidental finding of basal ganglia calcifications on computed tomography (CT) scan of the head. She was initially presumed to have Fahr’s syndrome in the context of idiopathic bilateral basal ganglia calcifications and psychotic features. Genetic testing performed revealed the deletion of 22q11.2, thus establishing the diagnosis of DiGeorge syndrome. This case highlights the importance of noticing subtle physical exam findings along with laboratory findings as this led to the diagnosis of DiGeorge syndrome for this patient. This case is unique in …

Exome Sequences Of Multiplex, Multigenerational Families Reveal Schizophrenia Risk Loci With Potential Implications For Neurocognitive Performance, Mark Kos, Melanie A. Carless, Juan M. Peralta, Joanne E. Curran, Ellen E. Quillen, Marcio Almeida, August N. Blackburn, Lucy Blondell, David Roalf, Michael F. Pogue-Geile, Harald H. H. Goring, Laura Almasy

School of Medicine Publications and Presentations

Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein-altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European-American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non-synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene-based …

Transcriptome Sequencing Study Implicates Immune-Related Genes Differentially Expressed In Schizophrenia: New Data And A Meta-Analysis, Alan R. Sanders, Eugene I. Drigalenko, Jubao Duan, Jessica Freda, Harald H. H. Goring, Pablo V. Gejman

School of Medicine Publications and Presentations

We undertook an RNA sequencing (RNAseq)-based transcriptomic profiling study on lymphoblastoid cell lines of a European ancestry sample of 529 schizophrenia cases and 660 controls, and found 1058 genes to be differentially expressed by affection status. These differentially expressed genes were enriched for involvement in immunity, especially the 697 genes with higher expression in cases. Comparing the current RNAseq transcriptomic profiling to our previous findings in an array-based study of 268 schizophrenia cases and 446 controls showed a highly significant positive correlation over all genes. Fifteen (18%) of the 84 genes with significant (false discovery rateo0.05) expression differences between cases …

Discovering Schizophrenia Endophenotypes In Randomly Ascertained Pedigrees, David C. Glahn, Jeff T. Williams, Joanne E. Curran, Harald H. H. Goring, Thomas D. Dyer, Anderson M. Winkler, Rene L. Olvera, Ravi Duggirala, Laura Almasy, John Blangero

School of Medicine Publications and Presentations

Background

Although case-control approaches are beginning to disentangle schizophrenia’s complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member’s risk as a function of shared genetic kinship with an affected individual, often referred to as the …

Characterizing Thalamo-Cortical Disturbances In Schizophrenia And Bipolar Illness, Alan Anticevic, Michael W. Cole, Grega Repovs, John D. Murray, Margaret S. Brumbaugh, Anderson M. Winkler, Aleksandar Savic, John H. Krystal, Godfrey D. Pearlson, David Glahn

School of Medicine Publications and Presentations

Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar …

Genetic Architecture Of Declarative Memory: Implications For Complex Illnesses, Carrie E. Bearden, Katherine H. Karlsgodt, Peter Bachman, Theo G. Van Erp, Anderson M. Winkler, David C. Glahn

School of Medicine Publications and Presentations

Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene …