Dan J Stein - US grants

DESCRIPTION (provided by applicant): The goal of this international collaborative project is to identify genes responsible for schizophrenia in the Xhosa population of South Africa. The three participating sites are Columbia University, New York (Ezra Susser, PI), University of Washington, Seattle (Mary- Claire King, Jack McClellan, Tom Walsh, MPIs), and University of Cape Town, South Africa (Dan Stein, PI). The vast majority of the genetic basis for schizophrenia has yet to be explained. We hypothesize that genes and pathways important to schizophrenia will harbor different, severe disease-causing mutations in different affected individuals. Given the genetic diversity of African populations, we expect to find genes for schizophrenia that have not yet emerged from studies of other populations. This project will also foster the development of gene discovery research for neuropsychiatric disorders in Africa. In 1100 Xhosa individuals with schizophrenia and 1100 age and gender-matched Xhosa controls, we will compare profiles of exomes, flanking regulatory sites, and noncoding RNAs (obtained by exome sequencing) and profiles of structural genomic variants (obtained by arrayCGH). Both rare/private variants and ancient African alleles will be identified and evaluated. Genes enriched for deleterious mutations in individuals with schizophrenia compared to controls will be defined as candidates. Variant profiles of candidate genes will be assessed in NIMH sequence databases derived from schizophrenia studies of other populations. This project will be the first to use modern genomic sequencing approaches to study schizophrenia in a population of sub-Saharan African lineage. If successful, our approach will identify genes important for the disorder in populations worldwide. These genes will stimulate future efforts to develop more effective treatment and prevention strategies.

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is unique among the psychiatric disorders, in that it requires an environmental exposure (trauma) for diagnosis, and is thus ideal for investigating the gene-environment (G x E) predictors of pathology1. Despite the high national prevalence of trauma, studies such as the South African Stress & Health Study (SASH) found that only 2.3% of South Africans suffer from PTSD in their lifetimes (2,3). PTSD and depression have been found to be highly co-morbid4,5 and there is evidence to suggest significant gender-related variation in these disorders2,6-9. Overall, females have been found to be at higher risk than males, which may be compounded by the high prevalence of intimate partner violence (IPV) perpetrated again women10-12. Pregnant women, in particular, have been shown to be particularly vulnerable to IPV and its adverse mental and physical health outcomes (10-12). While a number of studies have been conducted in the developed, high-income world to investigate the etiology of these disorders (13-21), there is a paucity of data in developing, low- to middle-income (LMIC) countries. Nonetheless, there is evidence to suggest an element of heritability in individuals with PTSD and co-morbid depression (4,6,22-29), which may be due to genetic predisposition or to environmental conditioning such as learned behaviour. In this study, we shall examine the hypothesis that vulnerability to PTSD and co-morbid depression results from interactions between specific candidate genetic polymorphisms and environmental/psychological risk factors, which combine to enhance the risk for PTSD and co-morbid depression following trauma. Pregnant female South Africans, aged 18-65, will be recruited from specified community health centres. Those who wish to participate will complete a battery of self-report measures, including the Modified PTSD Symptom Scale (MPSS), Childhood Trauma Questionnaire (CTQ), Beck Depression Inventory (BDI-II), MINI (Mini International Neuropsychiatric Interview) Depression Scale, Intimate Partner Violence (IPV) Questionnaire and Clinician-Administered PTSD Scale (CAPS). Each participant will also be asked to provide a saliva sample for DNA extraction and genetic analysis. Despite the adversity faced by many Africans and South Africans, some cope and function remarkably well. Thus, identifying genetic or other factors that allow these individuals t cope may elucidate the underpinnings of resilience, which could inform the search for novel preventative and therapeutic interventions for these prevalent and debilitating disorders.

? DESCRIPTION (provided by applicant): We are submitting this application to PAR-14-331, Global Brain and Nervous System Disorders Research Across the Lifespan (R21). The broad goal of this application is to build capacity and provide preliminary resources for the development of a research program aimed at understanding the influence of maternal trauma and posttraumatic stress on the development of brain and nervous system disorders on their offspring in South Africa with a focus on epigenetic mechanisms. This proposal is a collaboration between the Department of Psychiatry at the University of Cape Town (UCT) in South African, the Center for Molecular Medicine and Therapeutics at the University of British Columbia in Canada, and the Department of Epidemiology at the Columbia University Mailman School of Public Health (CU-MSPH). The proposed R21 will train South African partners in the bio-behavioral mechanisms, specifically epigenetic processes, via which maternal trauma and post-traumatic stress disorder (PTSD) impacts child development and collect preliminary data on such mechanisms in the Drakenstein cohort. The specific aims of this proposal are: 1) To expand capacity of South African collaborators to investigate epigenetic mechanisms underlying the impact of maternal trauma and post-traumatic stress across generations by formal training, regular meetings, professional meetings, an annual scientific symposium, and research experience. The goal of capacity building will be to prepare for the submission of an R01 application; 2) To identify DNAm signatures and associated biological pathways affected by maternal traumatic stress during pregnancy in infant cord blood. 3) To test whether infant cord blood DNAm signatures associated with maternal traumatic stress are correlated with delayed infant emotional development. This project capitalizes on the Drakenstein Child Study, a pregnancy cohort located at the University of Cape Town in South Africa that aims to investigate longitudinally the epidemiology and etiology of childhood pneumonia and the impact on child health by following1000 mother-child pairs through pregnancy and for the first 2 years of life with a planned data collection through age 7. The ultimate goal is the development of a new program of research crucial to the well-being of future generations of South Africans.

PROJECT SUMMARY/ABSTRACT Adolescent human immunodeficiency virus (HIV) and depression present significant public health challenges for South Africa, a country with the largest HIV epidemic globally and where structural factors including vio- lence and poverty increase susceptibility for poor mental health. In families already experiencing psychological distress, adolescents face elevated risk for sexually transmitted infections (STIs) including HIV and depres- sion. Preventive interventions are urgently needed during adolescence when risks for HIV, STIs, and depres- sion in-crease exponentially. Preventive intervention strategies for adolescents should substantively involve families who can tailor prevention content to meet the unique needs of individual adolescents and reinforce formation and habituation of prevention behaviors. Moreover, evidence indicates common family risk and pro- tective factors for adolescent HIV/STI risk behaviors and depression, underscoring the need for a family pre- vention approach. However, key gaps exist in family prevention science. In South Africa, few empirically sup- ported family interventions integrate prevention of HIV/STI with depression for adolescents. Our resilience-ori- ented approach engages families in adolescent prevention from low-resource settings facing high adversity. We focus on adolescents (14-16 years of age) who are at an ideal developmental transition for family engage- ment in prevention. Our age- and developmentally-tailored intervention ? called Our Family Our Future ? is based off of two empirically supported interventions that have been integrated and adapted to South Africa. In a pilot randomized trial, Our Family Our Future exhibited outstanding acceptability, feasibility and promising direction of effects including reductions of depressive symptoms; lower rates of sex; decreased unprotected sex; increased HIV testing; increased knowledge, motivation, intentions and self-efficacy for protective HIV/STI behaviors; improved family interactions; and increased resilience. Now we propose the next phase of this re- search program, an efficacy study of Our Family Our Future with three aims: (1) test the efficacy of the Our Family Our Future intervention in preventing HIV/STI acquisition among adolescents (14-16 years of age) with depressive symptoms by reducing HIV/STI risk behavior, and reducing depressive symptoms. The project will randomize N=880 adolescents to Our Family Our Future intervention or usual care with 6- and 12-month out- come assessments; (2) examine the extent to which the impact of the Our Family Our Future intervention is a) mediated by changes in resilience; behavioral skills; norms and attitudes relating to sex, condom use, gender; and family communication and functioning and b) moderated by the effect of sociodemographics, family HIV, and social protections; (3) identify barriers and facilitators to implementing Our Family Our Future within a large community-based organization setting with wide reach to provide data for future dissemination and scale-up. The study fills a significant gap in family prevention science in a priority population and setting and is aligned with the Trans-NIH Plan for HIV, NIMH, NIAID, and NICHD strategic research priorities. 

This collaborative project, between Emory University in the USA and the University of Cape Town (UCT) in South Africa, proposes to investigate biological mechanisms underlying the transgenerational effects of exposure to prenatal maternal psychological stress, anxiety, or depression. We propose to examine offspring gene expression as a potential contributor to this intergenerational association in this proposal. It has been suggested that a significant portion of fetal brain development occurs prenatally and this process may be influenced by maternal environment. Our recent work found that individuals with posttraumatic stress disorder (PTSD) and depression have reduced expression of DICER1 and selected downstream microRNAs (miRNAs). This stress-related DICER1/miRNA regulation pathway seems consistent in blood and brain in humans and mouse models. We hypothesize that this stress-related regulation pathway is also at play in young children being exposed to prenatal maternal PTSD and/or depression (PnM-PTSD/dep). We propose to extend our findings in the Drakenstein mother/child dyads through three aims. In Aim 1 we plan to compare DICER1 expression as well as genome-wide gene expression profiles between offspring cases (exposed to PnM-PTSD/dep) and offspring controls with no such exposure at birth. In Aim 2, we propose to examine genome-wide miRNA expression profiles between offspring cases and controls at birth. Through these aims, we hope to identify genes and pathways potentially implicated in the mechanisms underlying this intergenerational association. Through each of these aims, the proposal will build research capacity through training, site visits, collaborative data analyses, publications, and presentations. While the low-middle income (LMIC) site has some capacity in genomics research, it has very little capacity in the analysis of gene expression data; this grant will play a key role in building such capacity. Through collaboration between the LMIC and high-income investigators, we will lay the foundation - via infrastructure and collection of unique phenotypes and RNA data - for future studies of this unique mother-child cohort in the LMIC context.

PROJECT SUMMARY / ABSTRACT The broad goal of this application is to establish a trans-African neuropsychiatric genetics program that will ensure the genomics revolution in neuropsychiatry benefits future generations of Africans. Great strides have been made in our understanding of the genetic architecture of schizophrenia. Ultimately these advances will play a critical role in reducing the global burden of psychiatric disorders. However, African populations have been almost absent from neuropsychiatric genetics research and this poses a challenge for both scientific advance and global equity. Data from African populations in genetic studies of neuropsychiatric disorders are critical to generate a complete picture of genetic risk factors and identify potentially missing novel therapeutic signals garnered by studying all populations. The reduced correlation between markers in African populations is also useful for fine mapping disease-causing alleles. Beyond discovery, recent work on polygenic risk scores shows that potential for clinical utility of these measures, but also, vexingly, limited cross-population transferability and by extension poorer performance in uncharacterized populations such as those from Africa. There is also a significant risk that the recent advances in neuropsychiatric genetics will result in a widening of the massive research and treatment disparities between Africa and the rest of the world. To bridge this gap, we have initiated the NeuroGAP-Psychosis project, a collaboration with colleagues at Addis Ababa University in Ethiopia, Makerere University in Uganda, and the University of Cape Town in South Africa, with the goal of establishing a multi-national neuropsychiatric genetics research and training program in partnership with the Harvard T.H. Chan School of Public Health to accomplish the following specific aims: 1) Capacity building. Expand the capacity of African scientists to conduct large-scale genetic studies of schizophrenia and other psychotic disorders enabling the generation, analysis and interpretation of these data locally; 2) Clinical characterization. Validate tools for diagnosing and screening for schizophrenia and psychosis. Systematically characterize the clinical phenomenology of 13,000 patients with schizophrenia and psychotic disorders, including risk factors, symptom presentation, severity, medication use, substance use, and comorbid health conditions; 3) Genetic discovery. Perform the largest gene-discovery study of schizophrenia in Africa to date.In collaboration with local investigators, we will conduct genome-wide association studies of schizophrenia in ancestrally similar case/control populations. This proposal directly addresses the NIMH Strategic Plan goal 1.2 ?Identify the genomic and non-genomic factors associated with mental illness.? Our broad goal is to develop a sustainable research and training program aimed at addressing the major limitations in our knowledge of the genetic and environmental risk architecture of psychiatric disorders in persons of African descent and lead to improvement in diagnosis, prevention, and treatment in African and all populations.