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Center for Clinical and Translational Research (PI: Clore)KL2TR000057 Virginia Commonwealth University (VCU) seeks funding for an Institutional Clinical and Translational Science Awiard (CTSA). This opportunity comes at a pivotal phase in VCU's growth and development as a premier biomedical research institution and coincides with significant institutional commitment and direction recommended by the Board of Visitors. To accomplish the goals of the CTSA initiative, VCU has established a comprehensive matrix center, the Center for Clinical and Translational Research (CCTR). The CCTR will facilitate the development of new pailnerships and new initiatives that will extend our research base of fed- eral, private, and industry sponsored awards. Our already strong research program will be encouraged and abetted by a cultural transformation to support translational science and an influx of newly recruited multi- disciplinary investigators. The CCTR leverages substantial existing resources to encourage and support novel research methodologies at VCU. Emphasis is placed on three areas of research strength; namely substance abuse, women's health and rehabilitation science. Pilot funds will be awarded to support innova- tion and community engagement research in these areas. Architecture for a Clinical and Translational Data Environment, an enterprise data warehouse, and a collaborative web portal to facilitate data sharing across VCU, VCU Health System (VCUHS), other CTSA sites and national research networks has been developed A Research Incubator provides biostatistical support, facilitates research, encourages research in research ethics and provides guidance in regulatory issues. Strategies to enhance research subject participation, facilities for the conduction of human research, and access to the IVIid-Atlantic Twin Registry are described. Centralized management of and access to a rich array of research resources will be accomplished through the CCTR. Our students will enroll in trans-disciplinary educational cumcula which encourage team building including both a MS and a PhD in Clinical and Translational Science. CCTR will strengthen ties with our affiliates and community partners to make better use of their unique resources and respond to their needs.
Research Training: Psychiatric and Statistical Genetics (PI: Neale)T32MH020030 This application requests five further years of support for an Institutional National Research Service Award to cover multidisciplinary training in Psychiatric, Behavioral and Statistical Genetics. We request support for three pre-doctoral and three postdoctoral students for primary training in: i) statistical, quantitative, behavioral and molecular genetics~ ii) psychiatric nosology~ iii) neuroimaging genetics and neurobiology~ iv) clinical psychology~ iv) biostatistics. In addition to specializing in one of these areas, trainee will be exposed to all others and encouraged to study at least one other with sufficient detail to broaden their scope for future career development and interdisciplinary research. Training will usually be 4 years in duration for pre-doctoral and 2-3 years for postdoctoral students. Applications are expected from a wide variety of disciplines, including medicine, psychiatry, psychology, biostatistics, neuroscience, molecular genetics and biology. Trainees are housed in the Virginia Institute for Psychiatric and Behavioral Genetics at Virginia Commonwealth University, a modern custom-built facility with private offices, state-of-the-art computational facilities and integrated molecular genetics and experimental laboratories. Major strengths of the program include: i) broad expertise of faculty in psychiatry, psychology, genetics, neuroscience and statistics~ ii) highly productive research environment with well-funded faculty who are among the most highly cited researchers in the field~ iii) extensive experience and excellent track record of faculty in training at this level~ iv) potential for trainees to take pat in active data collection and data analysis projects~ v) access to large genetically informative datasets collected at VCU and elsewhere~ vi) direct access to genome sequencing, experimental study and neuroimaging facilities~ vii) pairing with clinical psychiatrist to attend rounds~ and viii) face-to-face instruction in responsible conduct of research from a leading author and instructor in this field.
Research Education in Statistical Genetics of Substance Use (PI: Neale)R25DA026119 This application seeks support from the National Institute on Drug Abuse R25 mechanism for pre-doctoral and postdoctoral research positions, infrastructure and workshops at the Virginia Institute for Psychiatric and Behavioral Genetics (VIPBG) at Virginia Commonwealth University (VCU). The overall goal of this research education program is to provide an environment for the innovative development and applications of statistical genetics methodology relevant to substance use, abuse and dependence (SUAD). Our research education program will be further developed with new courses in Statistical Innovation, Advanced Statistical Genetics, Epidemiology of Drug Abuse and Neuroscience to foster interdisciplinary research, a key component of NIDA's mission. The research education program consists of predoctoral and postdoctoral components. Pre-doctoral participants pursue degrees in Psychiatric, Behavioral and Statistical Genetics, Human & Molecular Genetics, Biostatistics or Computer Science. This component is designed to recruit potential future investigators to research in statistical genetics focused on SUAD. The aim is to create a cohort of PhD graduates who have been exposed to, and begun to publish research in, this area. The postdoctoral component recognizes that many promising researchers have training relevant to, but not focused on, the statistical genetics of SUAD. This flexible 2-3 year post doctoral training component guides young investigators to this field of study and provides them with integrated training that enables them to pursue careers in statistical genetics of SUAD. Research education is intended for individuals with training in mathematics, statistics, biostatistics, genetics, psychology, computer science or pharmacology and to those who have completed their clinical requirements for the MD degree. The postdoctoral component aims to educate independent investigators who contribute to efforts to identify and characterize the genetic and environmental determinants of SUAD, its development, prevention and treatment. Accordingly we: i) Offer and carefully monitor a multidisciplinary integrated research training program with a wide range of research opportunities; ii) Meet the needs for training in emerging research areas in SUAD; iii) Provide formal education and intensive mentoring to researchers from diverse academic and ethnic backgrounds; iv) Offer a specialized curriculum that merges strengths in SUAD research at our institution with training in methodological innovation; and v) Disseminate course materials, developed software, user guides and example scripts to the wider community by teaching workshops and maintaining a website with webcasts, podcasts and script libraries.
Epigenetic Associations of Treatment Outcome for Posttraumatic Stress Disorder (PI: Amstadter)NARSAD Independent Investigator Award
Stress-induced drinking in OEF/OIF veterans: the role of combat history and PTSD (PI: Amstadter)R01AA020179 Military personnel exposed to combat-related traumatic events, particularly those who develop posttraumatic stress disorder (PTSD), have a higher incidence of problematic drinking. However, little is known about the relationship between trauma, PTSD, and drinking in "emerging adults" (ages 21-30 years), in spite of this age group being at highest risk of developing subsequent drinking problems. The proposed clinical laboratory project will use a three group design. The target OIF/OEF population will have no trauma exposure [Control group], combat trauma exposure without PTSD [TE group], and combat trauma exposure with PTSD [PTSD group]. The type of traumatic event exposure history included will be limited to combat- related traumatic events that are interpersonal in nature. This project will use a well-established clinical laboratory paradigm of stress induction employed by our group, the Trier Social Stress Test (TSST), to investigate the role of a history of exposure to combat trauma on reactivity to the TSST and on stress- induced voluntary drinking. Subjects will not meet diagnostic criteria for alcohol dependence. Half of each group will receive the TSST and the other half will be randomized to the no stress condition. Using subjective as well as biological indices of stress, the first specific aim examines the effect of combat trauma history on stress reactivity, using subjective, neuroendocrine, and physiological measures of stress. The second specific aim will examine the effect of combat trauma history on subsequent drinking behavior and subjective response to alcohol using established procedures in a clinical laboratory paradigm. Exploratory analyses will also be conducted to examine the correlation between combat trauma history group and subjective response to stress, and combat trauma history group and drinking. Two additional exploratory analyses will evaluate the effect of the personality trait of distress tolerance (high and low), and the effect of carrying the 'S' or the rare 'LG' allele of the 5-HTTLPR polymorphism on the stress response and on voluntary drinking following stress induction. This study will advance our understanding of the relationship between a history of combat-related traumatic events, stress, and drinking. The ultimate goal of this line of research is to identify "at risk" groups early in their drinking careers, before unhealthy drinking practices and/or dependence develop. This information has the potential to inform prevention and intervention alcohol research.
Pathways to Alcohol Use Disorders in ALSPAC: A Genetic-Developmental Study (PIs: Kendler & Dick)R01AA018333 Pathways to Alcohol Use Disorders in ALSPAC: A Genetic-Developmental Study Alcohol Use Disorders (AUDs) emerge from diverse genetic and environmental risk factors acting through a range of complex developmental pathways. Very few studies exist that have a combination of sample size, representativeness, and sufficiently frequent and detailed assessments over the requisite age range to provide a realistic opportunity to disentangle these intricate etiologic pathways. The Avon Longitudinal Study of Parents and Children (ALSPAC) is such a study. Beginning with over 13,000 pregnant mothers ascertained around Avon England, the ALSPAC project has conducted detailed follow-ups of this sample for the last 16 years. The sample is now entering the critical transitional period from adolescence to young adulthood. This application, prepared by a team of investigators from Virginia Commonwealth University and University of Bristol, has three specific aims in the ALSPAC cohort. The first aim is to add detailed assessments of alcohol use and symptoms of AUDs to questionnaires already scheduled to occur at ages 18 and 20. This will allow us to capture a key developmental phase for alcohol use and the emergence of early symptoms of AUDs. The second aim is to conduct an extensive series of analyses seeking to understand the etiologic pathways to alcohol use (AU) and alcohol use problems (AUPs). The specific goals of these analyses will be (1) to characterize patterns of AU and AUPs across adolescence; (2) to identify childhood risk factors that predict AU and AUPs in adolescence and to understand the developmental processes by which these risks unfold; (3) to study the further development of these risk factors across adolescence and their interaction with emerging AU and its consequences; (4) to test the moderating role of gender on patterns, predictors, and developmental processes related to AU and AUPs; and (5) to extend models of risk for AU and AUPs into young adulthood using the age 18 and 20 data collected under Aim 1. The analyses will examine how risk unfolds across development across three major domains: Externalizing, Internalizing, and Environment (and how these eventually relate to AU and the development of AUPs). Each of these domains is broad, and one of the goals of the project will be to parse these constructs and delineate the most relevant risk dimensions. The third aim of the project is to incorporate information about a limited set of previously validated risk genes into developmental models of risk for AU, AUPs, and AUDs developed in Aim 2. This will be accomplished using molecular genetic data available on at least 3,000 subjects from the ALSPAC cohort at no cost to NIH. These analyses will allow us to study the dynamic interplay of biological, psychological, and social processes that contribute to pathways of risk (and resiliency) for AU and AUPs. With its large sample size, representativeness, detailed and frequent phenotypic assessments and availability of genotypic data, the ALSPAC cohort provides a unique opportunity to clarify, in a developmental context, the complex web of susceptibility and protective factors for AUDs.
Genetic and Environmental Risk Factors for Violent Criminal Behavior: A Swedish Twin Study (PI: Kendler)NR-SS-0102-12
A Longitudinal Study of Genes, Environment and Alcohol Misuse in College Students (PI: Kendler)R37AA011408 The general design of the field work for the VCU Student Survey (VSS) is simple. For each new freshman cohort, we will attempt to obtain a completed questionnaire early in the fall of their freshman year and a saliva collection for DNA. Then we will obtain a second questionnaire in the spring of their freshman year. Using funds from the prior years of this MERIT award, we have funded the first questionnaire and DNA collection in the 2011 freshman cohort this fall and will complete with available funds their second questionnaire in Spring 2012. In this extension, we will ascertain new freshman cohorts in 2012 and 2013 and then follow-up these three cohorts yearly through the completion ofthis project in 2017. Our goal for this extension is to further our knowledge ofthe genetic and environmental risk factors for problem drinking in late adolescence and the progression in young adulthood from problem drinking to full blown AUDs. Our 6 specific aims are: 1) to ascertain new Freshman VCU cohorts in 2012 and 2013 with computer based questionnaires & DNA collections and, along with the 2011 cohort already studied, follow them with yearly surveys up through Fall, 2016. 2) To complete our GWAS analysis of AUDs in the Irish sample and participate in meta-analysis of AUD GWAS sponsored by NIAAA; 3) To conduct extensive epidemiological and longitudinal analyses in the VSS with the goal of clarifying the action and interaction of key risk and protective factors for early problem drinking and to compare and contrast these results with those obtained using parallel measures in the ALSPAC cohort; 4) To genotype the VSS samples using the Affymetrix Exome + 50K custom SNP array, an efficient means to assess functional variation systematically across the MAF range as well as important candidate variation targeted by prior studies. 5) To screen at the level of SNPs, genes and gene networks, the association between molecular variation in the VSS and risk for early drinking problems and symptoms of AUDs and to compare these results with those obtained with parallel measures in the ALSPAC cohort; 6) To develop models integrating molecular variants and environmental risk factors in predicting early drinking problems and symptoms of AUDs in the VSS.
The Molecular Genetics of Recurrent Major Depression in Chinese Women (PI: Kendler)R01MH100549 Major depression (MD) accounts for substantial worldwide morbidity and mortality. Risk for MD is strongly influenced by genetic risk factors. This project seeks to elucidate the molecular basis of the genetic risk for MD by combining the rich phenotypic measures and sequence data from the CONVERGE (China, Oxford and VCU Experimental Research on Genetic Epidemiology) project. CONVERGE obtained detailed structured interviews on 6,000 Han Chinese women with recurrent MD and 6,000 ethically matched screened controls. Furthermore, in order to interrogate the genome more broadly and more deeply than is possible with genotyping arrays, genotypes will be obtained from low pass (LP) whole genome sequencing. In a sample of the size of CONVERGE, the design provides comprehensive measurement of common variation together with variants at minor allele frequencies below 1-2%, which are poorly imputed from microarray data. LP whole genome sequencing and variant calling will be completed in 2012 using external funding. An ancestry matched sample of 5,000 cases of MD and 5,000 controls is available for replication. We request 4 years of support to conduct i) clinical-phenotypic, ii) molecular-statistical analyses, including gene X environmental interaction analyses with verified environmental risk factors, and iii) replication analyses. In addition to our large sample size, the CONVERGE project has six design features which maximize the probability that we will be able to clarify the nature of the genetic risk factors for MD. We have recruited i) only women who are of ii) Han Chinese ancestry and who have had iii) recurrent illness. For these women, we have carefully assessed iv) four key environmental risk factors and v) a very rich phenotypic profile including important co-morbidities. Finally, our controls are relatively elderly and have been carefully screened to ensure a low liability to depressive illness. The identification of genetic variants which impact o risk for MD would open up the possibility of understanding the pathophysiology of this disorder and developing new methods of treatment and prevention.
Cross-Species Investigation of Gene Networks for Ethanol-Related Behaviors (PI: Kendler)P50AA022537 Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute critically to susceptibility to AUDs likely a result of many variants each contributing modestly to risk. Genetic studies in animal models and humans have to date made slow progress in identifying genes individual risk variants. However, modern high-throughput approaches such as genome-wide association studies or genomic expression profiling promise to rapidly increase the pool of potential candidate genes influencing AUDs. This proposal for a P50 Alcohol Research Center presents a novel and highly integrated overall design to focus on both gene discovery and functional interpretation for the genetics of AUDs. This application is the outgrowth of a P20 Developmental Center grant that established the VCU Alcohol Research Center in 2009. Having made significant progress, we propose here to extend and enlarge that Center. Our approach includes three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes, rather than single genes; 2) A cross-species genetic and genomics analysis to validate candidate genes and networks affecting ethanol behaviors; 3) A highly integrative Center design with rapid data sharing across projects through a cross-species analysis pipeline to provide ranked gene lists or networks for further experimental validation in the component projects. We request five years of support for six research projects and pilot grants for genetic studies in mice, worms, flies, and humans. Three projects will be in human genetics with a novel clinical laboratory component for assessing targeted genetic influences on human behavioral responses to ethanol in a controlled environment. All projects will be supported by an Administrative Core, an Analytic and Informatics Core and a Rodent Behavioral Core. The scientific work proposed in these projects and cores are clearly greater than the sum of their parts, due to the highly interactive structure of the VCU-ARC components. The VCU-ARC is well positioned to become a national resource making major contributions to the advancement of our understanding of the etiology of AUDs and their prevention and treatment.
1/2 Cis and trans data integration to find mechanisms causing psychiatric disorders (PI: van den Oord)R01MH097283 The amount of data related to the biological causes of psychiatric conditions has grown exponentially. Integrating results from all these studies can advance mental health research by increasing statistical power to find biomarkers, reduce false discoveries due to platform-specific technical errors, and increase confidence in findings when multiple lines of evidence point to the same biological factors. Because data integration can involve heterogeneous datasets and biological relations, it also has a considerable potential to improve our understanding of disease mechanisms by elucidating the broader context in which biological factors co-act. This work proposed builds on the long collaboration and complementary expertise of the Van den Oord (VCU) and Sullivan (UNC) labs. The result is a highly coherent, rigorous, and innovative data integration strategy aimed at improving understanding of unique and shared disease mechanisms underlying schizophrenia, bipolar disorder, major depressive disorder, and autism. Specifically: (1) the data sources we will use are deep, comprehensive, and tailored to psychiatry; (2) we developed the MIND package (Mathematically-based Integration of heterogeNeous Data) that is based on a rigorous mathematical framework that allows data integration in a meaningful and statistically optimal fashion. Rather than relying exclusively on simulations, MIND was tested empirically using a large independent replication study showing that it identified biomarkers that would otherwise require far more samples or genetic markers; (3) as we developed methods that can perform independent tests of virtually any kind of biological relationship in all available datasets, diseae mechanisms can be studied in very large samples; and (4) we will make all results and software available via SLEP (Sullivan Lab Evidence Project) for power users and in an user- friendly implementation for end users. Successful completion of the proposed project will (a) allow end users ready access to sophisticated tools for data integration, (b) allow power users to adapt use these resources as they choose, and (c) make an important, high-impact contribution to better understand disease mechanisms underlying psychiatric disorders.
A longitudinal methylome study to detect biomarkers predicting MDD trajectories (PI: van den Oord)R01MH099110 Major depressive disorder (MDD) is a leading cause of the global disease burden with a life time prevalence of almost 15%. Genetic studies have not worked as well for MDD as for other psychiatric conditions. DNA methylation studies are a particularly promising complement. First, methylation markers may have better predictive power as methylation is directly related to gene expression. Second, methylation studies may improve disease understanding as they can account for a range of clinical disease features. For example, DNA sequence variants cannot explain the variability in age of onset or the dynamic course of MDD that is typified by exacerbations and remissions. DNA methylation studies potentially can as methylation levels show age-dependent changes and are dynamic in post-mitotic tissues in the brain. Third, the translational potential of methylation studies is profound Methylation sites are excellent modifiable targets for pharmacological interventions and as methylation is stable and can be measured cost-effectively in blood they can potentially be used in clinical settings. Our overarching goal is to identify methylation markers in existing periphera blood samples associated with clinical MDD trajectories over a six year time period. Although methylation marks in blood will not directly impact MDD, factors that affect trajectories (e.g. stress) may also affect methylation signatures in blood. As traces of these methylation changes may be preserved during cell division, indirectly our studies can also shed light on causal mechanisms. Methylation of human (non-stem cell) DNA occurs at CpG sites. As the biological knowledge is lacking to identify good candidate CpG sites, we will use next-generation sequencing to screen the >28 million CpGs in the human genome for their association with the persistence of MDD, and then replicate the top findings in independent samples using a different technology. Specifically, we will sequence 1,500 methylomes using DNA collected from the same subjects at baseline and after six years from three groups from the Netherlands Study of Depression and Anxiety: 1) controls with no MDD, 2) cases with MDD at baseline and then fully remit, and 3) cases with chronic MDD. To improve statistical power and to select the biologically most meaningful methylation markers, we will integrate other data such as genome-wide transcriptome data that is already available for these samples. Using a parallel longitudinal 3 group design, the 50 most promising sites will be replicated in 1,500 independent samples using a different technology. Successful completion of the proposed research will yield replicable methylation signatures of MDD disease trajectories with which we will start generating prediction algorithms that could eventually be used in the clinic to improve prevention, treatment, and diagnosis.
Developmental methylomics of childhood trauma and its health consequences (PI: van den Oord)R01MH104576 By age 16, close to 2 children in 3 have suffered at least one adverse experience such as parental death, life-threatening illness, or family violence. Adversities have been robustly linked to an array of psychiatric and other medical conditions where the consequences can persist far into adulthood. The medical costs, mental health utilization, societal cost, and the psychological toll on its victims are tremendous. It is not wel understood how early adverse experiences are biologically embedded and what processes might be set into effect that would sustain long term health risks. To address these key questions we need prospective, longitudinal studies that begin in childhood and continue into adulthood and where data on adverse experiences can be linked to biosamples collected before and after adverse experiences as well as in adulthood. We propose just such a study, using already available samples from the Great Smoky Mountains Study (GSMS) and DNA methylation as the biological mechanism of interest. Methylation involves the addition of a methyl group to DNA and, in human non-embryonic cells, occurs mainly at CpGs. Animal and human research have shown that adverse events can result in persistent methylation changes with long-term phenotypic consequences. Capitalizing on these observations we propose a comprehensive study in a real life setting. First, we will use next-generation sequencing (NGS) to assay all >28 million CpGs in the human genome to study adversity-induced methylation changes and their persistence over time. To avoid false positive findings caused by pre-existing "case-control" differences (e.g. personality related or environmental factors such as poverty) we use a design that considers within-subject changes before and after DSM-IV extreme stressor events. Random assignment to trauma being impossible, this "natural experiment" is arguably the next best option this topic in children. Consistent with a model assuming a mediator role of methylation, we will select only the methylation sites that changed as a result of adversity for association testing with health risks. For the substantive and methodological reasons, we propose to treat maltreated children as a separate group in these analyses. Finally, we will replicate the 175 top findings in independent samples using a different and targeted technology to minimize the risk of false positives due to sampling and/or possibly technical errors. Successful completion of this project implies that we gained insight into how childhood adversities alters the methylome and what changes persist over time. We will also have identified processes associated with health risks in childhood/adulthood and found replicable methylation biomarkers associated with these risks. Methylation markers are stable and can be measured cost-effectively in blood, which is relatively easy to collect. Our findings therefore als have considerable translational potential as, for example, diagnostic "biomarkers of health risk" that could guide intervention strategies.
Gene-environment interplay in the development of alcohol use and related problems (PI: Dick)R01AA015416 This is a competing renewal of "Gene-Environment Interaction in Adolescent Alcohol Use" (R01AA015416), a new investigator research grant that used data from a longitudinal, population-based Finnish twin study to characterize the extent and nature of gene-environment interactions on substance use and externalizing behavior across adolescence. Our analyses demonstrated that etiological factors impacting substance use and externalizing behavior in adolescence vary profoundly as a function of the environment. In this competing renewal, we propose to use data now available on the twins in the young 20s (range 21-27 years) to characterize gene-environment interplay across the transition to young adulthood. The young 20s is a period of critical change as new environments become developmentally relevant (e.g., romantic partnerships, continuation vs. cessation of education, joining the workforce, having children). It also represents a critical time for the development of risky alcohol use behaviors and the onset of problems. This application, prepared by a team of investigators from Virginia Commonwealth University, the University of Helsinki, and Indiana University, has three specific aims. The first aim is to use twin data to characterize gene-environment processes (both gene-environment correlation and interaction) on substance use and externalizing behavior in young adulthood. The second aim is to conduct a series of exploratory analyses aimed at understanding how gene-environment interaction effects identified in twin data can inform our understanding of GxE effects associated with measured genes. We will test whether environments that moderate latent genetic risk in the twin analyses also moderate the association between specific individual genotypic risk and outcome. The third aim is to test the generalizability of identified gene environment interaction effects in a second, independent sample, the Virginia Twin Study of Adolescent Behavioral Development, with phenotypic data collection across a parallel age range from adolescence to young adulthood, and GWAS data. Together, these analyses will advance our understanding of how genetic and environmental influences come together to contribute to substance use patterns during the high-risk young adulthood developmental phase.
Collaborative Study on the Genetics of Alcoholism (site PI: Dick)U10AA008401 The Collaborative Study on the Genetics of Alcoholism (COGA) is a tightly integrated and interdisciplinary project that involves participation of investigators from multiple sites spanning a broad range of expertise. The goals of COGA are to identify and characterize genes in which variations confer risk for, or protection from, the development of Alcohol Use Disorders (AUDs) and related phenotypes; to understand the mechanisms by which these variants work at the molecular and cellular level; and to understand how genetic, environmental, and neurocognitive factors interact to influence the developmental trajectories of alcohol use and AUDs through an ongoing prospective study of at-risk individuals. COGA has assembled a unique sample of large, ethnically diverse families densely affected by AUDs and a set of comparison families, with rich phenotypic assessments in multiple domains: clinical, behavioral, neurophysiological, neuropsychological and environmental. The overall specific aims are to: Aim 1. Advance understanding of complex phenotypes related to AUDs; Aim 2. Identify additional genes contributing to risk for AUD, related phenotypes, including endophenotypes; Aim 3. Explore potential mechanisms of action of key genes; Aim 4. Examine effects of genes and environmental influences on clinical and neurophysiological phenotypes related to the vulnerability for risky drinking, AUDs and SUDs across development. In responding to the RFA, the study has three inter-dependent projects and three essential cores. The three projects are each focused on different aspects of these core aims: Genetic and Functional Studies of Alcohol Use Disorders and Related Phenotypes - Using a range of alcohol-related phenotypes, identifies variants across allelic spectrum and studies their mechanisms of action; Prospective Study of Genetic and Environmental Influences on Alcohol Use and Disorders Across Development - Longitudinally studies genetic and environmental influences and their interaction on development of AUDs during adolescence and emerging adulthood; Neurophysiological Phenotypes, Brain Maturation and Development of Alcohol Use and Related Disorders - Identifies genes related to novel neurocognitive phenotypes and their effects on trajectories of neurocognitive development and AUDs. The cores (Administrative Core, Data Management Core, and NIAAA/COGA Sharing Repository Core (NCSR)) provide critical support to each project, ensuring that key cross-study and cross site functions are centralized. Through tight coordination of this interdisciplinary study, we will go from identifyin genes, in which variants affect risk for AUDs and related phenotypes to understanding how they act at multiple levels, from molecular and cellular, to behavioral, neurophysiological, cognitive phenotypic, as a function of development. The delineation of the pathways and genes contributing to alcohol use and AUDs will impact treatment and prevention of AUDs in those at greatest risk. For more information about this study and a description of the dataset please see Wiki - COGA
Connecting Familial and Sporadic Schizophrenia By Exome Sequencing and Population Imputation (PI: Riley)NARSAD Senior Investigator Award: Exome sequence 170 Irish multiplex family schizophrenia cases, combine these data with exome 80 existing multiplex family case and genome (4908 population controls) sequence data from the United Kingdom, 3) impute sequence variants into 515 remaining family members, 1606 sporadic cases and 1755 population control samples and 4) analyze data in the total sample of 685 family members, 1606 sporadic cases and 6753 population controls to identify variation increasing disease risk.
Genetic Contributions of Negative Valence Systems to Internalizing Pathways (PI: Roberson-Nay)R01MH101518 Internalizing disorders (ID) represent the largest domain of emotional disturbances that affect the general population. In recent years, significant effort has been put into examining and defining basic dimensions of functioning (e.g., neural or physiologic) that cut across internalizing disorders as traditionally defined by current nosology. Thus, the goal of the current study is to examine relationships between measures constructed to probe negative valence system (NVS) expression (e.g., fear, anhedonia) in a genetically informative adolescent twin sample. This design allows for the examination of the interplay between genetic and environmental factors as a way of elucidating causal mechanisms involved in the NVS and the role the NVS plays in pathways to internalizing symptoms and syndromes. Within this design we will administer an informative suite of well-validated dimensional measures that tap into the NVS, focusing on five related constructs including anxiety, fear, stress, sadness/anhedonia, and irritability. The influence of genes on psychopathology changes such that different developmental stages are associated with a unique pattern of risk factors representing a dynamic interplay between development, genes, and environment. For this reason, we will target a critical developmental period, focusing on the transition that begins during the late teen years and proceeds into young adulthood. This transition will involve moving away from home/family and established peer networks for approximately half of the general population. For these individuals, a number of significant environmental changes will occur that will impact their emotional functioning and trajectory of internalizing symptom expression. Thus, measuring NVS before this unique developmental period from a genetically informed perspective is ideal for determining the shared and specific contributions of genes and environment to NVS expression and its influence on ID development.
Early-Onset Major Depression and Genome-Wide Methylation Patterns (PI: Roberson-Nay)NARSAD Independent Investigator Award: A genome-wide methylation analysis via pyrosequencing methods will be performed to elucidate epigenetic processes associated with mood disordered pathways. A discordant twin design, where twins differ on early-onset major depression, will be used.
Genetic influences on developmental heterogeneity of alcohol use disorder (PI: Edwards)K01AA021399 The overarching goal of this K01 proposal is to explore genetic influences on the developmental heterogeneity of alcohol use disorder (AUD). AUD affects a substantial proportion of US adults, is associated with a variety of psychiatric and medical problems, and represents a significant and costly burden to human health. Research indicates that AUD liability is a function of both genetic and environmental factors, which contribute to wide variation in the manifestation of problems. Epidemiological studies strongly suggest that the development of alcohol problems and related behaviors begins in adolescence, and culminates in the various "types" of AUD described in the alcohol research literature. An improved understanding of the etiology of AUD can contribute to efforts in prevention, intervention, and treatment by advancing the ability to identify problems early in development and address them in a targeted, appropriate, and effective manner. This proposal delineates a series of training and research goals for the candidate in an effort to advance the understanding of the developmental heterogeneity of AUD and clarify how genetic influences contribute to this variation: i) the candidate will establish expertise in the development and manifestation of AUD through clinical experience in both inpatient and community mental health treatment settings; and through structured readings and discussions with the mentor and co-mentor; ii) a variety of longitudinal modeling methods will be employed to explore the development of alcohol use/misuse alongside associated behaviors from adolescence to early adulthood, culminating in a phenotype that captures an individual's likelihood of membership in different developmental pathways to AUD (e.g., one associated with impulsive behavior, another with depressive symptoms, etc.); iii) genome-wide association studies (GWAS) will be conducted on the phenotypes constructed using longitudinal modeling. The candidate will develop skills in a host of sophisticated secondary analyses including gene-based, network-based, and ontology-based analyses, as well as more global assessments of genomic risk such as the construction of polygenic risk scores and exploration of the heritability of different pathways to AUD; and iv) the candidate will capitalize on previously established expertise in Drosophila genomics to establish a translational program of research, wherein promising candidates identified through the secondary analyses of GWAS data will be validated in a Drosophila alcohol sensitivity/tolerance paradigm. Subsequently, the application of bioinformatic and molecular genetic techniques in Drosophila will be used to generate additional candidates for further exploration in human genomic data. The institutional environment is ideal for the candidate's goal of developing a comprehensive program in alcohol research, and the proposed research represents an important contribution toward advancing the understanding of AUD through a combination of clinical, epidemiological, genomic, and translational methods, consistent with the mission of the NIAAA.
Depression, Inflammation, and Diabetes: Exploring Shared Etiopathology (PI: Mezuk)K01MH093642 Epidemiologic and clinical studies have established that Major Depression (MD) often co-occurs with medical conditions in later life, including metabolic disorders such as Type 2 Diabetes Mellitus (hereafter referred to as 'Diabetes'). It is now acknowledged that the inter-relationship between MD and Diabetes is likely bi-directional. Indeed, there is consistent evidence from population-based cohort studies that MD is associated with increased risk of and mortality from Diabetes and cardiovascular disease. However, prospective studies cannot definitively distinguish whether MD is a unique risk factor for metabolic disorders, or if this phenomenon is due to a common factor shared by both MD and Diabetes such as genetic liability, environmental stress, or systemic physiologic deregulation. Functional genomics, particularly assessment of gene expression, offer a novel means of specifying how environmental exposures intersect with genetic liability to influence physiology. The broad objective of this Career Development Award (K01) is to investigate the etiologic relationships between co-occurring MD and Diabetes, in particular the structural and relative contributions of genetic and environmental sources of risk. This research utilizes complementary approaches to investigating the aims below: first, the broad genetic and environmental pathways underlying this comorbidity will be examined using latent variable twin modeling; second, gene expression arrays will be used to examine specific biological pathways by which depressive symptoms influence Diabetes risk. The specific aims of the research plan are to: 1) evaluate environmental and genetic contributions, and their interaction, of the relationship between MD and Diabetes in later adulthood; 2) investigate the behavioral pathways linking MD and Diabetes while accounting for shared genetic liability; and 3) examine the relationship between depressive symptoms and expression of immune-related genes. The candidate will receive training in responsible conduct of research, genetic epidemiology, and functional genomics. The candidate proposes to implement this research plan during a period of closely mentored training with experts in psychiatry, immunology, functional genomics, epidemiology, and biostatistics. The proposed training plan will promote her transition to independence as an epidemiologist focused on exploring an integrative model of the psychological, behavioral, biological, and genetic aspects of mental health. The research plan addresses the intersection of two common and debilitating health conditions, Major Depression and Diabetes, that are leading sources of healthcare costs and public health burden in the US and globally. The public health significance of this research centers on understanding the etiologic relationships between mental and physical health in order to develop comprehensive programs to improve the health of persons with psychiatric disorders.
Diabetes, Depression, and the Contextual Environment: A Multilevel Analysis (PI: Mezuk)R21DK096375 Epidemiologic and clinical studies have established that Major Depression (MD) often co-occurs with medical conditions in later life, including Type 2 Diabetes Mellitus (T2DM). The relationship between MD and T2DM is likely bi-directional. Indeed, there is consistent evidence from population-based cohort studies that MD is associated with increased risk of and mortality from T2DM, and that T2DM is associated with onset and recurrence of MD. However, prospective studies cannot definitively distinguish whether MD is a unique risk factor for T2DM, or if this phenomenon is due to a common factor shared by both MD and T2DM such as genetic liability or environmental context. The goal of this study is to utilize a large, population-based sample to prospectively investigate the dynamic roles of the contextual environment, familial genetic risk, and their interplay on the development of comorbid T2DM and MD. Data come from Swedish national multi-generational inpatient, outpatient, and pharmacy registries, which have been linked to a nationally-representative sample of primary care centers in Sweden representing over 1 million individuals, collected since 2001. These data have been geocoded to neighborhood-level physical and social contextual environment data. This research utilizes multi-level longitudinal and structural equation modeling to investigate the specific aims, which are to: 1) investigate the association between contextual environmental characteristics (e.g., neighborhood socioeconomic deprivation, crime, proximity to parks or fast food restaurants, social disorganization) and comorbid T2DM and MD; 2) examine the familial genetic contributions to the comorbidity between T2DM and MD; and 3) examine the interplay between genetic risk and the contextual environment on development of T2DM and MD. Genetically-informative designs provide a unique opportunity for exploring competing etiologic models of the relationships between the contextual environment and genetic risk for comorbid T2DM-MD. Using family designs we can estimate an individual's genetic liability for T2DM and MD, and thus conduct a more direct and unbiased examination of the contextual environmental factors that contribute to this comorbidity. This application aims to explicitly incorporate contextual environmental factors into our understanding of how genetic liability is expressed and moderated by the environment, and the findings will provide insight into the broad etiologic mechanisms of how environmental context influences risk of T2DM and MD. Public health significance: The research plan addresses the intersection of two common and debilitating health conditions, T2DM and MD, that are leading sources of healthcare costs and public health burden in the US and globally. Understanding the dynamic roles that genetic risk, environmental context, and their interaction play in development of comorbid T2DM and MD will inform innovative programs that reflect this complexity in order to more effectively promote public health and guide clinical care.
Pathways from Normal and Disordered Personality to Substance Use Disorders (PIs: Kendler & Gillespie)R01DA037558 Chronic substance use (SU) and licit and illicit substance use disorders (SUDs) are debilitating and contribute substantially to global morbidity and mortality. Personality and personality disorders strongly influence risk of SU and SUDs, but we know little about the etiologic pathways involved. This project utilizes a unique resource to address a number of novel research questions concerning SU and SUDs. We will use state-of-the-art genetic epidemiological methods to identify causal and non-causal pathways from normal, abnormal and pathological personality to licit and illicit SU and SUDs using the longitudinal, phenotypically rich, and genetically informative population-based Norwegian Twin Registry (NTR). We will link the NTR data to national, population-based and clinical registries, using Norway's unique personal identification number to study the risk factors, causes and disease mechanism as well as consequences of licit and illicit SU and SUDs. This will enable validation and identification of unreported SUD cases. The registry data will also provide objective information on demographics, socioeconomic status and psychosocial dysfunction as measured by sick leave, disability, and illness thereby enabling us to determine the causal and non-causal pathways from SU and SUD to psychosocial dysfunction. Our project has 6 scientific and one operational aim. We will use cross-sectional and longitudinal data to estimate the nature of the phenotypic associations between disinhibitory normal, abnormal and pathological personality types, SU and SUD, and correlated Axis I disorders before decomposing the associations into genetic and environmental pathways. Using complementary approaches we will model direction of causation between our key variables, while testing meditational models to clarify the role of SU as a gateway to SUDs and correlated externalizing spectrum disorders. Using genetically informative longitudinal models we will explore the causal relationship between alcohol use disorders and major depression. We will also merge NTR twin data with data from Statistics Norway to examine the phenotypic and genetic pathways from SU and SUDs to objective psychosocial dysfunction as indexed by nationwide sick leave, disability and illness. Our operational aim is to ascertain a new, fourth wave of questionnaire data on lifetime SU and SUDs from the NTR twins. This will provide statistical power to test competing longitudinal models. The modelling expertise of the collaborative group will ensure optimal exploitation of these resources. This application is submitted under a special funding mechanism "Norwegian Collaborative Projects with Research Groups in the United States" established and cofounded by the NIH and the Research Council of Norway. We propose to study how genetic and environmental risk factors in normal, abnormal and pathological personality impact and predict the risk of SU and SUDs by linking new and existing data from the NTR to national, population-based demographic and clinical registries. The same data will provide objective information on how SU and SUDs are related to sick leave, illness and disability.
Stress-Induced Drinking in Returning Soldiers: Genetic and Epigenetic Mechanisms (PI: Amstadter)K02AA023239 The purpose of the present K02 Independent Scientist Award is threefold: first, to provide structured career development activities in psychiatric, statistical, and molecular genetics, second, to deepen my knowledge of alcohol-related phenotypes, and third, to apply these skills to the analysis of the rich genomic data yielded from my current R01, my other funded projects, as well as other data available at my institute. These goals stem directly from my funded projects and represent expansions in my current areas of expertise. Specifically, although I have the skill set needed to meet the genetic Aim of my current NIAAA R01 (AA020179 "Stress- induced Drinking in OEF/OIF Veterans: the Role of Combat History and PTSD" which is ongoing) I need increased training to fully utilize the data to ask new and deeper questions that are on the cutting edge of alcohol genetics research. Since my original training (in candidate gene designs) the field of genetics has changed significantly and increased in sophistication (e.g., genome wide association [GWAS] platforms, exom arrays, methylation arrays). These new platforms have introduced a number of analytic complexities, with multiple decision points in every stage of the process, from data cleaning to analysis to the interpretation of results. Thus, this K02 will give me the skills in the integration and harmonization of genomic data on multiple platforms (e.g., sequence, methylation, expression) to better utilize (beyond the original, now outdated aim) my NIAAA R01 data on the genomic influences on stress reactivity and subsequent alcohol use in soldiers. This aim will be achieved by hands-on training in molecular and epigenetics (including wetlab immersions), supervised statistical genetic analyses done in collaboration with leaders in the field, formal coursework and workshops, and individual tutoring by K02 consultants. Additionally, the K02 will deepen my expertise in the area of alcohol-related phenotypes, beyond stress-induced drinking, which has been the focus of my work to date. This aim will be achieved through directed readings, formal coursework, practical experience analyzing relevant datasets (e.g., NIAAA R37011408 "A Longitudinal Study of Genes, Environment and Alcohol Misuse in College Students"), and mentorship from leaders in the field (Dr. Kenneth Kendler). In summary, the overarching goal of the proposed K02 is to further my multidisciplinary independent program of research which aimed at the identification of risk and resilience factors, both biologic and psychosocial in nature, for traumatic stress related conditions (alcohol use disorders [AUDs], posttraumatic stress disorder [PTSD]) and translation of these findings into prevention and intervention programming. The K02 will provide me with protected time to fully engage in the training activities I have outlined, enabling me to coalesce my diverse training background and move my research program forward in ways not previously possible.
A Twin Study of Negative Valence Emotional Constructs (PI: Hettema)R01MH098055 Internalizing disorders, consisting of syndromes of anxiety and depression, represent common, debilitating conditions, the etiology of which is not well understood. Neuroscientists have developed dimensional assessment instruments and psychological tasks that probe negative valence systems as alternative phenotypes to clinical symptoms. Such alternative phenotypes are under consideration for use in the NIMH's Research Domain Criteria (RDoC) project. However, little is currently known regarding their genetic basis and how that relates to internalizing risk factors. This study will extend and deepen our understanding of the relationships between such alternative phenotypes and early manifestations of ID symptomatology. The approach will be to administer an informative suite of dimensional measures and experimental tasks to 500 pre-adolescent twin pairs from a large epidemiological sample. These subjects will also be assessed for current and lifetime internalizing psychopathology and a broad array of childhood risk/ protective factors. The expected outcome is to provide novel insights into the mechanisms by which genes and environment confer risk to internalizing disorders via these more basic phenotypes that putatively reflect underlying affective processing.
Using Novel EQTL-Based Methods to Find the Molecular Causes of Alcohol Dependency (PI: Bacanu)R21AA022717 To contribute to the understanding of the molecular basis of alcohol dependence, we i) attempt to increase the power of detecting genetic signals by developing methods to analyze all functional variants in a gene jointly and ii) use such developed methods to discover and replicate genetic findings from available alcohol related data. In this proposal we focus on expression Quantitative Trait Loci (eQTLs). To achieve the goal of testing eQTLs jointly, we propose to i) construct a tissue specific data base of eQTLs found in dense genotype panels, e.g. 1000 Genomes Project (1KG), ii) develop two statistical methods which use this database information and implement them into fast user friendly software, iii) discover promising genes by applying the developed methods to publicly available alcohol use disorder (AUD) studies and iv) replicate discovered genes in a proprietary AUD study. In the database we include all 1KG genetic variants which are known or predicted to influence gene expression in tissues relevant for AUD, i.e. brain and liver. Both proposed methods have the major advantage of using only summary statistics, i.e. they do not require access to subject level genotypes. The first method directly imputes the univariate summary statistics at unobserved eQTLs based on 1) univariate summary statistics at measured variants nearby and 2) the correlation structure, as estimated from a relevant reference population. The second method uses the univariate statistic at measured and imputed eQTLs, to derive the test for the joint effect on phenotype of all eQTLs in a gene. These methods are subsequently used to discover and replicate findings using summary statistics from data sets which are both publicly available and proprietary. For the discovery phase, we use all the publicly available summary data sets, such as Collaborative Study on the Genetics of Alcoholism among others. We replicate the discovered genes using the internally available Irish Alcohol Study.
Using Genetic Overlap to Dissect the Genetic Architecture of Psychiatric Diseases (PI: Bacanu)R21MH100560 This project seeks to contribute to the understanding of the genetic basis for schizophrenia (SCZ) and bipolar disease (BD). To achieve this goal, we attempt to amplify genetic signals of modest effect in an SCZ/BD cohort, by analyzing such a cohort together with a well powered study of another (relevant) phenotype. The strategy relies on clarifying etiologic pathways to illness by looking at overlaps with a genetically well characterized correlated trait - in this case height (H). Large scale epidemiological studies suggest that increased H is associated with a decreased risk of SCZ. Given that BD is comorbid with SCZ, H might share (as suggested by our pilot analyses) causal pathways with each of these two psychiatric disorders. The genetic meta-analysis of H is probably the largest to be published, which ensures that it has good power to detect even modest genetic signals. Thus, H is a good candidate for a phenotype to be tested for genetic overlap with SCZ/BD, where by genetic overlap we mean the SNP/genes which significantly affect both phenotypes, not just one. Critically, this overlap can allow us to clarify etiologic pathways to SCZ/BD that might be quite difficult to detect in other ways. Furthermore, we suggest that our method can yield at least two classes of etiologic pathways. We provide preliminary evidence that pathways where the genetic effects on the two phenotypes are concordant (i.e., in the same direction) are very different from pathways where they are discordant. Thus, we suggest that, to avoid pathway heterogeneity, it is advisable for the concordant and discordant signals to be analyzed separately in pathway analyses. To uncover a part of the genetic architecture of SCZ/BD we employ a two steps process using only publicly available univariate summaries from relevant meta-analyses. In the first step we evaluate i) the genetic overlap of each disease with a) H and b) between SCZ and BD. In the second step, the most promising concordant and discordant overlap signals are used in separate gene set analyses to uncover whether these signals are enriched in certain molecular pathways. To assess the overlap between SCZ/BD and H, we develop novel statistical methods to i) increase the genetic data resolution by imputing summary statistics at unobserved SNPs based only on the summary statistics at observed SNPs and ii) obtain the genetic overlap between multiple phenotypes which is not overly influenced by a strong signal coming from just one phenotype.
Convergent Genetic and Genomic Analyses of Bipolar Disorder (PI: Fanous)I01BX001242 Objective: To identify common and rare genetic variants which increase the risk of bipolar disorder (BP). Specific Objectives: 1. To discover both rare and common risk variants for BP by sequencing the whole genome of one affected individual from the 6 highest-density PIC families and the 36 highest-density families from the NIMH Genomics Initiative (42 patients in total), at ~32X coverage using second-generation short read DNA sequencers. 2. To rank the genes with greatest accumulations of deleterious variants discovered in SO 1 using a combination of bioinformatics criteria. We will implement an algorithm which prioritizes variants on the basis of functional changes and other features (e.g. exonic and promoter regions, and micro-RNA and transcription factor binding sites). This will be done in two steps: a. First, for variants discovered in regions linked to BP in that subject's family, and then b. In the rest of the genome. 3. Determine the complete DNA sequence of the 5 most promising genes in 500 BP cases and 500 normal controls by genome partitioning with Long PCR and second-generation short read DNA sequencers. 4. Impute novel variation into several large BP GWAS datasets. Currently, this only includes the Psychiatric GWAS Consortium (PGC, 7,481 cases and 9,250 controls). The Genomic Psychiatry Cohort and VA CSP#572 samples are also projected to be available. NB: This step will involve no new laboratory work or clinical assessments, but will only use existing GWAS marker data at that time. Background: Bipolar disorder is a major cause of disability amongst US veterans as well as worldwide. However, very little research in the genetics of BP has been done in the VA system. A number of genomewide association studies have reported several novel risk genes for BP but still explain only a small proportion of the genetic risk. Whole-genome sequencing has emerged in the last 2-3 years as the most comprehensive method to detecting genetic variation, and has recently resulted in several published findings of novel causes in several disorders. While prohibitively expensive only a few years ago, next-generation sequencing technologies have now made whole-genome sequencing possible, and it is currently being applied to complex diseases such as psychiatric illnesses. Proposed Methods: We plan to sequence the whole genomes of 42 patients with BP using the Illumina HiSeq 2000. To maximize the chance of identifying causative variants, these subjects will come from families in which there are at least 3 affected siblings. We will compare the genome sequences of these subjects to the sequence data in the 1000 Genomes Project, which is publicly available. We will prioritize sequence variants discovered based on their function. Based on our preliminary data, we expect to find thousands of deleterious variants which will not have been documented in established databases such as dbSNP. The 5 genes with the highest levels of deleterious variation will be sequenced in 500 cases and 500 controls using long PCR. Finally, we will attempt to impute the variants we discover in several large existing GWAS datasets, including one currently being collected in the VA system nationwide.
Genes and Molecular Pathways in Nicotine Dependence and Withdrawal (PI: Miles)R01DA032246 Despite evidence of strong genetic contributions to the etiology of smoking initiation (SI) and nicotine dependence (ND), we are far from identifying the specific genetic basis of individual susceptibility to ND. This project - to deepen our understanding of how genes contribute to risk for nicotine dependence (ND) - has arisen as an effort to utilize maximally the relatively unique and complementary set of skill of this group of investigators in complex human genetics, animal genetics and nicotine pharmacology. We will validate these putative risk genes using a two-step approach: replication in other human samples and the demonstration in animal models of ND that variants in these genes contribute to neurobiological pathways likely involved in ND. We will first identify promising candidate genes for smoking initiation (SI) and ND by data-mining GWA datasets and the selected candidates will be replicated. Using a mouse model of nicotine withdrawal, we will characterize behavioral QTLs relevant for ND using a recently developed expanded BXD RI mouse strain panel, focusing on strains informative for already identified areas of provisional QTLs. This approach allows us to both validate and refine our mapping of the nicotine behavioral QTL. Furthermore, we will identify candidate genes for ND by combining expression and behavioral genetics analyses in these BXD RI mouse strains. Candidate genes/pathways identified and prioritized from human and mouse studies will be validated by pharmacological or genetic manipulations to alter expression or function of candidate genes in mouse brain and determine effects on behavioral responses to in models of nicotine reward and withdrawal.
Of Mice and Primates: Gene Networks in Excessive Ethanol Consumption and Anxiety (PI: Miles)U01AA016667 An underlying premise of the INIA-Stress consortium is that progression to abusive ethanol consumption is, at least in part, accompanied and perhaps caused by alterations in an organism's response to stress, including the stress of excessive ethanol intake/withdrawal. We propose that changes in brain gene expression networks are an important part of allostatic mechanisms leading to progressive ethanol consumption and aberrant responses to stress. We have previously used genetic and genomic approaches across brain regions of BXD recombinant inbred panel to define robust gene networks regulated by acute ethanol and relate these to ethanol behaviors, particularly regarding responses to stress. We have also identified significant overlap in expression responses to acute ethanol in mice and altered gene expression patterns seen in a primate model of excessive ethanol intake (SIP) developed by Dr. Grant, the PI of the INIA-Stress consortium. Furthermore, very recent pilot array studies in BXD mice exposed to multiple cycles of the chronic intermittent ethanol vapor (CIE) model of excessive ethanol consumption have identified remarkable homology with results from acute ethanol exposure and our data from cynomolgus macaque. Those studies have generated gene networks that allow testing initial major "hub" genes for their possible role in modifying ethanol consumption and response to stress in the CIE model. For example, we recently identified Gsk3p as an important regulator of ethanol consumption and withdrawal-induced anxiety, using AAV viral vector gene delivery studies. Based on these findings, we propose the following Organizing Hypothesis: Altered ethanol drinking and stress/endocrine phenotypes in the mouse CIE and monkey SIP models result from (and cause) adaptive responses in brain gene expression networks, resulting in a new allostatic set point. The aims of this project will define new gene networks underlying allostatic changes in the CIE and monkey SIP models by expression profiling of CIE treatment across the BXD mouse panel and Rhesus Macaque samples of Dr. Grant (Project 1), co-analysis of results with RNA-Seq data of Dr. Williams' Project 10, and testing of candidates, including Gsk3P, using viral vector gene delivery.
Understanding the Genetic Architecture of Schizophrenia in Chinese Population (PIs: Chen & Kendler)R01MH101054 Schizophrenia is a severe mental disorder with significant genetic effects. However, the nature and the identity of the genetic factors remain elusive. Recent genome-wide association studies (GWASs) have made substantial progress, identifying several promising candidate genes with common variants. However, these candidates only account for a small proportion of observed heritability. More recently, sequencing and copy number variation (CNV) analyses have documented many rare de novo mutations associated with the risks to this disorder. Combined with what we have learned from GWASs, it is clear that both common and rare variants contribute to genetic risks to schizophrenia. Our current knowledge of schizophrenia is overwhelmingly derived from the study of Caucasian populations. The limited investigations of other ethnicities and the lack of systematic examination of the differences between populations are noticeable in the field. These weaknesses may impede our understanding of the etiology of the disorder. In responding to the request for application AI- 12-021 "U.S.-China Program for Biomedical Collaborative Research (R01)", we propose studies aiming at the understanding of the genetic architecture of schizophrenia in the Han Chinese population and investigating the shared and ethnic-specific risk factors between the Han Chinese and Caucasian populations. Our aims are: 1. to conduct exome sequencing for 140 nuclear Han Chinese families with multiple affected individuals to discover single nucleotide variations (SNVs) and copy number variations (CNVs) predisposing to the disorder. We plan to use families with both parents (affected or unaffected), 2 affected and 1 unaffected siblings and families with 1 parent, 2 affected and 1 unaffected siblings. The use of families with affected and unaffected siblings allows us to simultaneously discover and characterize transmitted and de novo risk variants. The unaffected siblings in the families are better controls than subjects from the general population, as they can help to distinguish potentially pathological variants from many benign variants observed in the families. 2. To genotype 5,000 cases and 5,000 controls of Han Chinese samples for up to 100 of the most promising risk variants discovered in Aim 1 above to verify their association with SCZ. We will apply a set of sophisticated statistical, bioinformatics and functional filters to select the most promising SNVs. We will focus on those rare variants (including de novo variants) with potential functional consequences and variants occurred at multiple sites in the same genes and biological pathways. 3. To perform comparative analyses using GWAS datasets from both Caucasian and Han Chinese populations to estimate the overlap of genetic risk between the two populations, and to discover and characterize the shared- and ethnic-specific risk genes. We propose to use polygenic analyses to examine the correlation between the PGC and Chinese GWASs to estimate the overlap of risk factors between these populations, and to examine the genetic structure of SCZ in these two ethnic groups.
Developmental Genetic Epidemiology of Smoking (PI: Maes)R01DA025109 This project aims to increase our understanding of the etiology, development, heterogeneity and comorbidity of smoking by examining both individual and contextual influences. It focuses on adolescents, who are at greatest risk for smoking initiation (SI) and in whom prevention and control of smoking persistence (SP) would have the greatest potential benefit to public health. The last decade has seen tremendous growth in quantitative statistical methods for complex traits, and in large genetically informative epidemiological samples, which now allow us to test critical complex questions. We have access to three longitudinal genetically informative data sets of adolescent twins and their parents, six data sets with published adolescent smoking data and three extended twin (ET) kinship studies. Detailed data on smoking behavior are available in one adult and in three adolescent/young adult twin samples. Data are from the United States, Belgium, the Netherlands, Finland, Australia and Sweden. We will test the following hypotheses about SI: 1) SI in early adolescence is primarily influenced by shared environmental factors; genetic factors gradually contribute more to liability to SI in later adolescence and young adulthood, 2) the rates of SI vary by culture (US, Europe, Australia), but variance components do not, 3) the influence of parents and parental smoking decreases and that of siblings and peers increases from adolescence to young adulthood, 4) the influence of measured environmental factors gradually decreases and that of measured genes (identified in GWAS) increases over adolescence, 5) the effect of measured genes on SI varies as a function of environmental factors (GxE), 6) the role of genes and environment is the same for males and females. The second set of hypotheses concerns the relationship between SI and SP/ nicotine dependence (ND). We will test whether 7) there is significant but not complete genetic and environmental overlap between SI and measures of SP & ND in adolescence/ young adulthood, 8) there is significant measurement variance by age and sex for SP/ND, 9) the same genes and environments influence SI and SP throughout adolescence, 10) there is genetic overlap between SI, age of onset of SI and between age of onset and SP/ND, 11) the contribution of environmental risk factors is greater to SI than to SP/ND, and 12) the contribution of measured genes (identified in GWAS) is greater for SP/ND than for SI. Our access to rich developmental (prospective and retrospective) data sets and our expertise in statistical modeling of genetically informative samples, puts us in a unique and ideal position to address these specific aims. Doing so will substantially improve understanding of how nature and nurture interact to generate liability to smoking.
Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity (PIs: Jackson-Cook & York)R01AG037986 Psychosocial influences have been implicated in the etiology of several of the most common illnesses impacting human health (cardiovascular disease; diabetes; cancer). It has been hypothesized that these psychosocial effects are mediated through DNA-based biological changes, such as methylation alterations or telomere attrition. However, due to the paucity of research in this area, many questions remain: To what extent do epigenetic and acquired genomic changes accumulate over the human lifespan? Do childhood adversities result in biological changes that persist into adulthood? Can an adult who was exposed to childhood adversities be identified as "at risk" for developing disease based on their epigenetic, gene expression, telomeric, chromosomal instability, and/or cortisol level profiles? To answer these questions we will study 736 twins who have completed intense phenotypic behavioral evaluations in previous studies (completed 2 to 15 years ago) and represent two risks groups: (1) twins experiencing the extreme childhood adversity event of sexual abuse; and (2) twins experiencing a broad spectrum of social experiences. Cohort 1 (ages 40-55) will comprise a selected sample of 50 identical twin pairs who are discordant for a history of childhood sexual abuse, as well as 50 identical concordant pairs who did (25 pairs) or did not (25 pairs) experience sexual abuse as a child. The biological endpoints that will be measured and compared between co-twins for this cohort include: (1) frequencies and locations of genome-wide methylation changes using a sequence-based approach; (2) chromosome-specific telomere lengths; (3) frequencies of acquired chromosomal instability; (4) patterns of gene expression; and (4) diurnal basal salivary cortisol levels. Cohort 2 (ages 20-30) will be comprised of a normative sample of monozygotic (157 pairs) and dizygotic (111 pairs) twin pairs for whom behavioral phenotypes have been carefully determined throughout adolescence into young adulthood. The data gained from the study of these twins will provide insight as to the potential cumulative effect of multiple adversities on embedded biological changes. The biological endpoints to be measured for this cohort (for whom blood samples have been previously collected and are readily available) include: (1) frequencies and locations of genome-wide methylation changes using array based methodology; and (2) gene expression patterns. Collectively, comparisons of observed alterations in biological endpoint measures (within and between twins) to phenotypic data collected from multiple stages in the human lifespan will allow us to deduce the extent to which the observed differences in biomarkers are influenced by childhood adversity, adult adversity, and/or other environmental stressors. The data from this investigation will lead to the first direct estimate of the frequency of epigenetic, telomere length, acquired chromosomal instability, gene expression, and/or cortisol level changes that arise in adults due to childhood adversities.
Racial Differences in Epigenetic Mechanisms of Preterm Birth (PI: York)P60MD002256 Sub-Project 6463 Preterm birth is more prevalent in African Americans than European Americans and contributes to 3.4 times more African American infant deaths. Models of social inequity do not appreciably account for this marked disparity and molecular genetic studies have yet to characterize whether allelic differences that exist between races contribute to this gap. It has been hypothesized that the effect of social and environmental determinants of health (SEDH) are mediated through DNA-based epigenetic changes, such as methylation. However, due to the paucity of research in this area many questions remain: To what extent do SEDHs result in biological changes that influence liability to preterm birth? Can a pregnant woman be identified as "at risk" for a poor pregnancy outcome based on her epigenetic, gene expression profiles and history of SEDHs? To answer these questions we will study 200 pregnant African American and European American women recruited through VCU Medical Center clinics. These women will be prospectively tracked at defined intervals throughout pregnancy to measure a broad array of social, economic, behavioral and stress-related measures and obtain blood, decidual and placental tissue samples for methylation, gene expression and genotype studies. The analytic strategy will take advantage of a longitudinal, repeated measures design to identify robust, causal environmental-biological mechanisms that both influence preterm birth and account for racial differences in preterm birth rates. The goals of the three specific aims are to: 1) identify robust environmental and biological predictors of preterm birth; 2) integrate these predictors to identify causal environmental-biological mechanisms of preterm birth and; 3) quantify the extent to which these predictors and mechanisms account for the overrepresentation of preterm birth in African Americans. Three specific aims are proposed: Aim 1: Employ data reduction and prioritization methods to develop a set of optimal environmental and biological measures and identify those constructs that correlate with preterm birth. Aim 2: Identify causal mechanisms of preterm birth that integrates environmental and biological risk factors through epigenetic processes. Aim 3: Determine if the influence of race on preterm birth persists over and above the mechanisms identified in Aim 2.
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800 E. Leigh St., Biotech One
Richmond, VA 23219-1534