Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) commonly co-occur and are likely to increase in prevalence following the COVID-19 pandemic given the vast health, psychiatric, and economic toll this pandemic is causing particularly among persons of color. Understanding risk and protective factors for AUD and PTSD is critical to inform effective prevention and intervention planning; these conditions have shared latent genetic risk as well as a molecular genetic correlation, and the onset of one condition may increase risk for development of the other condition and thus multi-method studies that integrate shared genetic and phenotypic risk are needed. The present study will conduct a multi-method investigation of PTSD and AUD among a highly trauma-exposed at-risk population of inner-city residents for whom the COVID-19 pandemic may be particularly impactful for to rigorously test models of comorbidity thereby shedding light on these important public health.

Childhood trauma exposure, particularly in the form of interpersonal violence, increases risk for alcohol use disorder (AUD), posttraumatic stress disorder (PTSD) and their co-occurrence, perhaps through complex interactions of molecular genetic risk, and trauma-related disturbances in neural development; however, knowledge is limited in this area due to limitations of prior research, including lack of longitudinal data in multiple domains and reliance on outdated genetic designs. Using cutting-edge statistical genetics techniques and results from existing “big data” genome wide association studies, aggregate genetic risk scores indexing risk unique and common to these disorders will be integrated into sophisticated longitudinal analyses of adolescent and young adult neural connectivity and risk for adult AUD and PTSD. Results from this study will shed light on these important public health conditions and will yield important implications for prevention and intervention efforts.

The overarching goal of this proposal is to understand the genetic relationships between Substance Use Disorders (SUD, i.e., alcohol, nicotine, cannabis, opioid) and Posttraumatic Stress Disorder (PTSD) while increasing representation of individuals of diverse ancestry in psychiatric genetics research. The immense framework of the Psychiatric Genomics Consortium (PGC) will be used to allow for scientific collaboration, phenotypic harmonization across thousands of participants through the PGC-PTSD and PGC-SUD workgroups, and for building upon the success of each group in ancestral diversity. This research will increase understanding of the etiology of PTSD and SUD, informing prevention and intervention efforts tailored to those with co-occurring PTSD and SUDs and moreover will increase inclusion of individuals of African and Latinx descent in large-scale genome-wide association studies.

Much remains unknown about the causes of persistent post-concussive symptoms (PPCS) following mild traumatic brain injury (mTBI). Genetic research is promising in the early stages. Combining this with what is known about genetic risk for other post-combat conditions that often co-occur following mTBI, posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), is a needed next step. We aim to understand the make-up of cumulative genetic risk for PPCS, PTSD, and AUD, how they are related, and how they can help predict risk for these outcomes over time and in combination with the environment. To do so, we will use large-scale genetic data along with data from a large study of service members and veterans.

The BioInformatics and Analysis (BIA) core is responsible in helping human and animal project researchers to analyze their data and to synergistically integrate the results from all this projects

We are assessing the differences in gene expression between miRNA (and their target genes) in postmortem brains of subjects with and without a diagnosis of major depressive disorder.

We will advise perform analyses of the miRNA-Seq data, as well as in the analyses and interpretations of the SNP effects on miRNA expression.

We will work on GWAS and other genetic analyses for the adverse effects of antipsychotics in veterans.

Anxiety disorders are quite common, chronic, and disabling. Both genetic factors and exposure to environmental stress contribute to their development. The identification of the genes that play a role in their development can provide new clues to their causes and new directions for prevention and treatment research.

Alcohol consumption (alcohol quantity x frequency/AQF), Alcohol Use Disorders (AUDs) and posttraumatic stress disorder (PTSD) often co-occur, and there is emerging evidence that shared genetic risk may partially account for the high rates of this co-occurrence. This project seeks to clarify the shared molecular genetic underpinnings of the PTSD-AQF/AUD co-occurrence, while testing two key laboratory-based phenotypes (i.e., distress tolerance and anxiety sensitivity) as potential predictors, and socioeconomic status and social support as moderators of genetic effects. This K01 award will provide the candidate with the necessary training to become an independent, federally-funded investigator in the intersection of traumatic stress-related outcomes, laboratory-based paradigms, and psychiatric and statistical genetics.

Improved understanding of the causal mechanisms of how early life socioenvironmental factors influence neurocognitive development and risk phenotypes for substance use disorder may help identify novel therapeutic targets. This application proposes to establish a multidisciplinary and functionally diverse team and generate preliminary data in rats towards improving our understanding of behavioral biomarkers and genetic risks factors of neurocognitive behaviors related to substance use disorder risk.

Down Syndrome Regression Disorder (DSRD) is a devastating condition that is being increasingly identified and is of growing interest in the Down syndrome (DS) community. This study aims to recruit a large cohort of caregivers of adolescents and young adults with DS to develop and validate the Down Syndrome Regression Rating Scale, a novel low-burden assessment tool to aid in the screening and monitoring of DSRD.

This project seeks to clarify the mechanisms by which alcohol and substance use disorders are related to risk of suicidal behavior. We will apply a range of novel and sophisticated methodological approaches, using data from Swedish national registries. Given close parallels between substance misuse and suicidal behavior across Sweden and the US, these findings have the potential to identify targets for prevention and intervention.

The specific aims of this project will leverage recent advances in the molecular genetics of suicidality to clarify the mechanisms by which aggregate genetic liability relates to suicidal thoughts and behaviors. We will use seven independent samples to explore how genetic liability exerts its effects across the life course via behavioral mediators and in the context of environmental exposures. This integrative approach will provide critical psychosocial context to biological findings.

Non-suicidal self-injury (NSSI) and suicidal behaviors are correlated but distinct outcomes, and how they are etiologically related remains unclear. This study aims to assess how a range of sociodemographic, behavioral, and environmental predictors are similarly or differentially related to NSSI and suicidal attempt in a large, population-based study, to clarify shared etiology. We will further assess the impact of aggregate genetic risk for correlated outcomes (substance misuse, major depression, personality) on these distinct outcomes.

Major depression (MD) is a leading cause of disability worldwide, arises from the action and interaction between genetic and environmental factors, and is often comorbid with other psychiatric and medical conditions. Although recent progress has yielded modest insight into the genetic architecture of MD, most studies have been in European ancestry populations, seriously limiting our knowledge of human genomic variation, disease etiology, and precision medicine efforts. Here, we propose cross-population genetic studies of MD to advance our understanding of the genetic architecture in all populations and ensure that genetic research is broadly applicable.

Co-morbid Major Depressive Disorder (MDD) increases risk for Alcohol Use Disorder (AUD) and unique genetic factors may contribute to AUD risk depending on MDD status. Furthermore, men and women display disparate patterns of temporal development of AUD with co-morbid MDD and their genetic liabilities for the disorders may be different. This project therefore proposes a plan of research considering innovative models to analyze sex-specific genetic and environmental effects on AUD at the item level to contribute to filling the current gap in scientific understanding of the mechanisms by which MDD and sex effects interact with common variants genetic signal to predispose to AUD.

Multiple genetic risks cause alcohol, nicotine and cannabis substance use (SU) and substance use disorders (SUDs). However, genetic studies alone cannot explain the cascade of molecular changes between SNPs and SU and SUDs. Nor can current approaches correctly measure the causal impact of genetic differences on parental and home environments linked to SU and SUDs. Molecular studies that link GWAS results to gene expression data via eQTL findings have increased our understanding of the etiology of SU and SUDs. Yet, they fail to capture complex gene interactions that are the hallmark of complex traits including SU and SUDs, or are mostly underpowered (especially from brain tissues). Another limitation is that genetic and molecular studies neglect environmental confounding. We know that parents create and influence children's environments and that certain parental and home environments are more associated with SU and SUDs. Not only do genetic risks vary with environments, but environments themselves are also heritable, and are thus confounded by parental genetics. We and others argue that unconfounding the impact of parent-to-offspring molecular genetics on SU and SUDs from the parental and home environments is the central task of genetics. Here, we rely on recent methodological advances to address these limitations. First, we have developed a novel and proven method of measuring the impact of untransmitted parental genomes. This method identifies the indirect impact of untransmitted parental genomes on complex behaviours. A significant impact of untransmitted genomes is evidence of genetically nurtured environments that are unconfounded by the direct parent-to-offspring genetics.

This proposal will leverage the Asian Bipolar Genetics Network (A-BIG-NET), an international collaboration of investigators from the U.S., Taiwan, South Korea, Singapore, India and Pakistan, to carry out a molecular genetics study of bipolar disorder in East and South Asia. It will establish a valuable genetics resource with 4x low?pass whole genome sequence and rich phenotype data that will dramatically increase the worldwide diversity of genetics data on bipolar disorder, an important step to accelerate gene discovery in this disorder and advance global mental health equity.

The research proposed here will contribute to an understanding of the causes major depressive disorder, the commonest psychiatric disorder and a leading cause of disability throughout the world. The proposal will improve our ability to diagnose depression from electronic health records, generate insights into the genetic architecture of depression, separating out specific from non?specific genetic risk factors, and will identify, from the  analysis of sequencing data, genes that are involved in the etiology of the disorder. The research will provide newinsights into disease, and well enable the development of more effective therapy.

This project seeks to clarify the nature and significance of the heterogeneity of alcohol use disorder, to understand how the risk for the disorder is transmitted within couples, families, and large pedigrees, the nature and causes of alcohol related medical complications and the impact of acculturation on risk in immigrants. To meet these goals, we will apply advanced statistical methods to a unique set of epidemiological resources available in Sweden. The findings will be relevant to the US, with potential impacts on prevention, treatment and policy.

This project seeks to clarify etiologic pathways to aggregate drug abuse and opiate abuse more specifically. To accomplish this goal, we will utilize a unique and growing set of epidemiological resources available in the country of Sweden and a range of advanced statistical modeling methods. The resulting findings will be relevant to the US and other developed countries, with potential impacts on drug abuse prevention, treatment and policy.

Alcohol Use Disorder is a heritable, common and severe substance use disorder which carries substantial medical and social morbidity. Large sample genome wide association studies (GWAS) of other complex medical and psychiatric disorders have, with sufficient sample size, led to important insights into etiology which are being translated into new treatment and preventative measures. This project will collect a large sample of severely ill cases with Alcohol Use Disorder which, together with other parallel efforts, will identify key risk genes for this disorder which can, in turn, improve our understanding of its biological causes and open up new therapeutic opportunities.

This project will collect samples from 10,000 South Korean women with recurrent major depressive disorder and 10,000 matched controls. All subjects will be genotyped and the location of genetic risk factors identified in a genome-wide association analysis. The cohort will also provide detailed information about the likely environmental causes of depression, and when combined with a similarly deeply phenotyped cohort from China, will form a uniquely powerful resource for the discovery of genes involved in recurrent major depressive disorder.

This project seeks to clarify the etiology of key internalizing psychiatric disorders and closely associated functional medical disorders by applying a range of methods from epidemiology, genetic epidemiology and molecular genetics to the large informative population-based cohort in the Netherlands called Lifelines. We will attempt to understand the origins of the comorbidity between these disorders and how genes and environment contribute to their development. To meet these goals, we will apply advanced statistical methods to a unique set of epidemiological and molecular genetic resources.

The goal of this project is to explore the shared genetic liability between alcohol use/problems and suicidal thoughts and behaviors (STB). This shared liability underscores the existence of possible common mechanisms that would be involved in both alcohol use/problems and STB. Capitalizing on genetics and neuropsychology, we will explore how decision-making mechanisms can play a role in alcohol use/problems and STB co-occurrence, how genetic liability is involved in this association, and whether environmental factors may influence the development of decision-making and its relation with alcohol use/problems and STB. An improved understanding of these processes will contribute to prevention and intervention efforts by advancing our ability to target potentially modifiable mechanisms according to the influence of genes and environment.

This award supports the development of open educational resources for data science methods training. The newly created materials will be used to teach reproducible research methods and serve as the primary texts in the graduate-level data science courses HGEN611 and HGE612 at VCU.

The purpose of this grant is to address basic questions regarding the relationship between microRNAs (miRNAs) and the pathophysiology of major depression in adolescence. We will assess the composition and stability of miRNA expression levels in peripheral blood samples from young adults. This information will inform the design of future investigations to obtain a comprehensive map of RNA expression profiles during adolescence and provide pilot data to assess multi-omic longitudinal models of risk for depression onset that incorporate behavioral, genetic, and epigenetic variables.

This proposal aims to investigate the genetic architecture of psychotic symptoms as they present in schizophrenia, schizoaffective disorder, and bipolar I disorder using sophisticated statistical approaches to derive empirical phenotypes and perform genome-wide association testing in a multi-ancestry cohort.

Our goal is to better understand the emergence of adolescent substance use behaviors by testing the hypothesis that music engagement is associated with less substance use initiation and less frequent substance use. There is already evidence that music engagement interventions are effective for individuals with substance use disorders, and there are multiple reasons to expect these beneficial effects could extend to substance initiation in adolescence. By integrating state-of-the art genetic and longitudinal approaches that address key confounds, this work will quantify these potentially protective associations and provide critical groundwork for translational and intervention efforts targeted at supporting high-risk individuals before the onset of problematic substance use.

This project seeks to identify factors related to high resistance to substance use. Factors increasing resistance may have the highest impact in maintaining or leading to health, as opposed to disease. Identifying these factors requires novel methods developed for this study, and developmental data – from childhood to adulthood – already available and newly obtained in this project in a sample of twins.

Project Narrative There is a shortage of researchers with the high levels of interdisciplinary skills needed to make progress in understanding the etiology and improving clinical treatment of alcohol use disorder (AUD), a major public health problem. The objective of this training grant is to educate the next generation of researchers focused on i) elucidating the risk factors for and outcomes of problem alcohol use, ii) understanding the behavioral and molecular causes and consequences of problem alcohol use, and iii) contributing to the translation of these basic findings into improvements in both treatment and prevention of AUD. The training in this program aims to educate an interdisciplinary diverse work force of researchers with a solid knowledge of multiple relevant areas, including genetics, behavior, neurobiology, data science and clinical treatment who will be prepared to have an impact on the health of millions of individuals affected by AUD.

Persons from marginalized communities are underrepresented in biomedical research, both as participants and as actual biomedical scientists. This under-representation results in reduced perspectives on culturally-sensitive assessments for neurobehavioral and neuroscience research, and also impoverishes public health research initiatives that may benefit health of racial minorities. To improve inclusion, the Virginia Commonwealth University (VCU) site of the Adolescent Brain Cognitive Development (ABCD) study seeks supplemental funding to enable an immersive human-subject biomedical research experience to Olive Calonge, who is graduating from Stony Brook University Spring 2021, and who has expressed an interest in developmental neuroscience.

There is a shortage of researchers who have skills in both statistical or molecular genetics and psychiatric epidemiology. Such individuals are needed to increase our understanding of the causes and trajectories of psychiatric disorders, so that better prevention and treatments can be developed. This training grant will educate three pre-doctoral and three postdoctoral trainees in psychiatric, behavioral, statistical and molecular genetics and neuroscience.

The ABCD Study consortium uses multimodal brain imaging, cognitive and clinical assessments, bioassays, mobile monitoring, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning in 11,878 9-10 year-olds to be followed over 10 years, to determine the effects of substance use on adolescent brain and cognitive development. This ABCD Research Project Site will follow and assess participants enrolled in the study. These data will be shared with the,scientific community to address a comprehensive range of questions concerning youth development.

Substance use abuse and dependence are especially complex disorders, with innumerable genetic and environmental risk factors, highly variable patterns of onset, offset and comorbidity with psychiatric disorders, cardiovascular disease and cancer. This project will develop Mendelian randomization based statistical methods and software and apply them to unique data from the Netherlands on genomic methylation. The project will improve understanding of the causes and effects of substance abuse and dependence, and how best to prevent and treat these disorders and their sequelae.

Binge eating and bulimic syndromes are significant mental health problems that disproportionately affect women. Their pronounced psychiatric and medical morbidity underscore the urgent need to understand their development. Identification of the deleterious effects of combined oral contraceptives (COCs) on binge eating could substantially reduce the risk of bulimic syndromes in vulnerable women and spearhead a much more personalized medicine approach to COC use and prescriptions.

Alzheimer's disease is considered the most costly and burdensome disease in the U.S, and its public health impact will only grow with the increase of 65-75 year olds in the next decade. Paralleling cardiovascular disease and cancer, it is now widely recognized that a key to slowing disease progression is early identification during pre dementia phases. With cognitive and biomarker data beginning when participants were in their 50s, the longitudinal VETSA project stands to advance progress toward early identification, which may, in turn, improve quality of life and reduce societal burden.

Alcohol use disorder (AUD) affects millions of people in the US. Although genetic studies have identified loci associated with AUD, its genetic etiology has not been fully explained. This project aims to 1) develop integrative methods for analyzing large-scale genomic datasets of AUD to increase power for genetic discovery, and 2) elucidate the genomic architecture of AUD by using systems biology approaches.

Project Narrative Alcohol-induced analgesia is a phenomenon related to two major public health problems in the US: alcohol use disorder and pain conditions. Alcohol confers analgesic effects in a dose- dependent fashion, but the genes and networks underlying this heritable process are poorly characterized. In this training proposal we will study the genetic aspects of ethanol-induced analgesia in mouse models using the complementary, genome-wide methodologies of behavioral quantitative trait locus mapping, differential gene expression analysis in critical brain regions, and weighted gene co-expression network analysis.

The goal of the proposed pilot study is to aggregate and harmonize two existing, genetically informed datasets from deeply phenotyped laboratory studies of fear conditioning in trauma-exposed populations. This study will also leverage large-scale genome-wide association study (GWAS) summary statistics of PTSD and problematic alcohol use. Understanding how aggregate genetic risk influences laboratory intermediate phenotypes and AUD-PTSD risk has implications for understanding etiology, informing risk prediction, and supporting down-stream targeted prevention and intervention efforts.