Gustavo Turecki - US grants

Many individuals who lived through Hurricane Katrina experienced extreme levels of negative emotions (e.g., sadness, anger, anxiety) in the short-term, and some of these individuals will continue to experience these emotions in the long-term as well. However, not every individual from the affected areas will experience the same initial levels and course of emotions over time, and not every individual will cope with the disaster in the same way. This study will examine both psychological/behavioral resiliencies (e.g., sense of control, social support, coping, hope, personality) and molecular genetics influences (i.e., neurotransmitter systems, such as serotonin, that are known to influence emotions) that may affect the unfolding of emotional responses after experiencing the stress from Hurricane Katrina and its aftermath. As such, this study is poised to advance basic knowledge on fundamental "Nature-Nurture" questions and to explicate how bio-behavioral factors influence emotion regulation. In this study, the researchers will recruit and follow Hurricane Katrina survivors, now living in Columbia, SC, and community members who did not go through the Hurricane, to examine changes in basic emotions over time. Participants will be assessed at baseline for levels of negative and positive emotions, recent positive and negative events, and individual resiliencies; and genetic material will be collected and assayed. Following this initial assessment, individuals will report weekly for 3 months on levels of basic emotions as well as positive and negative events. Based on this multi-wave study, the researchers hope to understand how genetic and psychosocial factors influence trajectories of positive and negative emotions, and how evacuees are coping with the stress and aftermath from Katrina.

Results from this study have important implications for educating the broader society about how substantial, uncontrollable natural disasters affect emotional experience over time and how individuals' genetic and psychological factors operate and interact to regulate emotions. Disseminated widely, such information should be of immediate interest given society's desire for understanding how Hurricane Katrina survivors will cope, as well as the society's innate and enduring interest in learning more about "Nature-Nurture" issues.

[unreadable] DESCRIPTION (provided by applicant): This collaborative R01 involves three sites: New York State Psychiatric Institute/Research Foundation for Mental Hygiene, Inc., in New York City, USA (Mann), McGill University in Montreal, Canada (Turecki) and University of Munich, Germany (Rujescu) to examine the complex genetic basis of suicidal behavior. We have contributed to the original observations showing that suicide and nonfatal suicide attempts have biologic changes that are distinct from those of major psychiatric disorders that underlie suicide such as major depressive disorder or bipolar disorder. We have reported candidate gene associations that are independently associated with mood disorders or with suicide attempts. We believe the field is ready for a major effort to survey the genome to seek genes associated with suicidal behavior that are independent of the major psychiatric illnesses. We have developed and tested a potential predictive stress-diathesis model of suicidal behavior derived from a comprehensive assessment of risk factors. Depressed individuals with prominent (1) pessimism and (2) severity of life-time aggression/impulsivity are at greater risk for suicidal behavior and the effects are additive. These clinical phenotypic components can be measured in the field in patients and suicides. We now propose to use genome-wide screens to identify candidate genes and conserved haplotype blocks within those genes 4000 cases that span the higher severity range of suicidal behavior, namely completed suicide and attempted suicide compared to both psychiatrically matched controls and to healthy volunteers. We have data on Axis I and Axis II diagnoses and data on lifetime aggression scores and current severity of depression to permit assessment of these potential etiological factors and potential behavioral endophenotypes. We have data on childhood reported histories of physical or sexual abuse which will be a focus for an exploratory gene-early environment interaction analysis. Causal SNPs will be further identified by sequencing the most promising gene segments. PUBLIC HEALTH RELEVANCE: The predisposition to suicidal behavior is substantially determined by genetic factors independent of those associated with major psychiatric disorders. This study will screen the genome in the largest collection of samples ever assembled for such a study of suicidal behavior in order to identify the responsible genes. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Multiple interacting genes and environmental factors determine the risk and trajectory of drug addiction. Expression of genes involved in the risk and consequences of addiction is influenced by environmental factors that in many cases are likely to leave persistent chemical modifications (epigenetic marks) in DNA and chromatin. We propose to comprehensively identify in archived postmortem human brain, changes in gene expression and linked epigenetic marks associated with chronic cocaine dependence. We will study two dopamine-dependent brain regions, the dorsal and ventral striatum. We will profile epigenetic marks in cocaine abusers with both short and long-term drug exposures. For analysis of the transcriptome, we will perform whole genome, strand- specific sequencing of mRNA transcripts (RNA-seq). For the DNA methylome, we will use MeDIP or equivalent technology to map the distribution of methyl CpG's at genome- wide and locus specific levels. The ultimate aim of this proposal is to discover which epigenetic changes in brain accompany the transition from cocaine abuse to chronic cocaine dependence. Discovery of cocaine-associated networks and pathways will provide clues to the etiology of cocaine addiction and will identify likely points of intervention in molecular and biochemical pathways that represent potential therapeutic targets. PUBLIC HEALTH RELEVANCE: Multiple interacting genes and environmental factors underlie the risk of drug addiction. First-time high throughput technologies will be used to develop epigenome maps of human brain, which are essential for understanding how epigenetic mechanisms figure in the neurobiology of drug abuse. We will profile epigenetic marks in human brain from chronic cocaine abusers to better our understanding and treatment of drug addiction.