Gene-Environment Interactions and Depression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64289/1/Koenen_Gene Environment_2009.pd

Genetic Influences on the Neural and Physiological Bases of Acute Threat: A Research Domain Criteria (RDoC) Perspective

The NIMH Research Domain Criteria (RDoC) initiative aims to describe key dimensional constructs underlying mental function across multiple units of analysis—from genes to observable behaviors—in order to better understand psychopathology. The acute threat (“fear”) construct of the RDoC Negative Valence System has been studied extensively from a translational perspective, and is highly pertinent to numerous psychiatric conditions, including anxiety and trauma-related disorders. We examined genetic contributions to the construct of acute threat at two units of analysis within the RDoC framework: (1) neural circuits and (2) physiology. Specifically, we focused on genetic influences on activation patterns of frontolimbic neural circuitry and on startle, skin conductance, and heart rate responses. Research on the heritability of activation in threat-related frontolimbic neural circuitry is lacking, but physiological indicators of acute threat have been found to be moderately heritable (35–50%). Genetic studies of the neural circuitry and physiology of acute threat have almost exclusively relied on the candidate gene method and, as in the broader psychiatric genetics literature, most findings have failed to replicate. The most robust support has been demonstrated for associations between variation in the serotonin transporter (SLC6A4) and catechol-O-methyltransferase (COMT) genes with threat-related neural activation and physiological responses. However, unbiased genome-wide approaches using very large samples are needed for gene discovery, and these can be accomplished with collaborative consortium-based research efforts, such as those of the Psychiatric Genomics Consortium (PGC) and Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium. © 2015 Wiley Periodicals, Inc

The Role of Genes in Defining a Molecular Biology of PTSD

Because environmental exposure to trauma is the sine qua non for the development of Post Traumatic Stress Disorder (PTSD), the recent focus on genetic studies has been noteworthy. The main catalyst for such studies is the observation from epidemiological studies that not all trauma survivors develop this disorder. Furthermore, neuroendocrine findings suggest pre-existing hormonal alterations that confer risk for PTSD. This paper presents the rationale for examining genetic factors in PTSD and trauma exposure, but suggests that studies of genotype may only present a limited picture of the molecular biology of this disorder. We describe the type of information that can be obtained from candidate gene and genomic studies that incorporate environmental factors in the design (i.e., gene – environment interaction and gene-environment correlation studies) and studies that capitalize on the idea that environment modifies gene expression, via epigenetic or other molecular mechanisms. The examination of epigenetic mechanisms in tandem with gene expression will help refine models that explain how PTSD risk, pathophysiology, and recovery is mediated by the environment. Since inherited genetic variation may also influence the extent of epigenetic or gene expression changes resulting from the environment, such studies should optimally be followed up by studies of genotype

Incorporating the social environment in genotype environment interaction studies of mental disorders

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79175/1/j.1742-1241.2010.02359.x.pd

Socioeconomic and Other Social Stressors and Biomarkers of Cardiometabolic Risk in Youth: A Systematic Review of Less Studied Risk Factors

Background: Socioeconomic disadvantage and other social stressors in childhood have been linked with cardiometabolic diseases in adulthood; however the mechanisms underlying these observed associations and the timing of their emergence are unclear. The aim of this review was to evaluate research that examined relationships between socioeconomic disadvantage and other social stressors in relation to less-studied cardiometabolic risk factors among youth, including carbohydrate metabolism-related factors, lipids, and central adiposity. Methods: We searched PubMed and ISI Web of Science to identify relevant publications between 2001 and 2013.Studies were selected based on 4 criteria: (1) the study examined an association between at least one social or economic stressor and one relevant outcome prior to age 21; (2) the sample originated from a high-income country; (3) the sample was not selected based on a health condition; and (4) a central aim was to evaluate the effect of the social or economic stressor on at least one relevant outcome. Abstracts were screened and relevant publications were obtained and evaluated for inclusion criteria. We abstracted data from selected articles, summarized them by exposures and outcomes, and assigned an evidence grade. Results: Our search identified 37 publications from 31 studies. Socioeconomic disadvantage was consistently associated with greater central adiposity. Research to date does not provide clear evidence of an association between childhood stressors and lipids or carbohydrate metabolism-related factors. Conclusions: This review demonstrates a paucity of research on the relationship of socioeconomic disadvantage and other social stressors to lipid and carbohydrate metabolism-related factors in youth. Accordingly, it is not possible to form strong conclusions, particularly with regard to stressors other than socioeconomic disadvantage. Findings are used to inform priorities for future research. An improved understanding of these pathways is critical for identifying novel prevention targets and intervention opportunities to protect the long-term health of children and adolescents

Epigenetic modifications associated with suicide and common mood and anxiety disorders: a systematic review of the literature

Epigenetic modifications are those reversible, mitotically heritable alterations in genomic expression that occur independent of changes in gene sequence. Epigenetic studies have the potential to improve our understanding of the etiology of mood and anxiety disorders and suicide by bridging the gap in knowledge between the exogenous environmental exposures and pathophysiology that produce common mood and anxiety disorders and suicide. We systematically reviewed the English-language peer-reviewed literature about epigenetic regulation in these disorders between 2001–2011, summarizing and synthesizing this literature with respect to directions for future work. Twenty-one articles met our inclusion criteria. Twelve studies were concerned with epigenetic changes among suicide completers; other studies considered epigenetic regulation in depression, post-traumatic stress disorder, and panic disorder. Several studies focused on epigenetic regulation of amine, glucocorticoid, and serotonin metabolism in the production of common mood and anxiety disorders and suicide. The literature is nascent and has yet to reach consensus about the roles of particular epigenetic modifications in the etiology of these outcomes. Future studies require larger sample sizes and measurements of environmental exposures antecedent to epigenetic modification. Further work is also needed to clarify the link between epigenetic modifications in the brain and peripheral tissues and to establish ‘gold standard’ epigenetic assays

Risk Factors for Course of Posttraumatic Stress Disorder Among Vietnam Veterans: A 14-Year Follow-Up of American Legionnaires

Risk factors affecting the course of posttraumatic stress disorder (PTSD) are poorly understood. As part of a larger study on characterizing exposure to herbicides in Vietnam, the authors investigated this issue in a random sample of 1,377 American Legionnaires who had served in Southeast Asia during the Vietnam War and were followed over a 14-year period. High combat exposure, perceived negative community attitudes at homecoming, minority race, depression symptoms at Time 1, and more anger at Time 1 predicted a more chronic course. Community involvement at Time 1 was protective and associated with decreased risk at Time 2. Discomfort in disclosing Vietnam experiences was associated with an increased risk for developing PTSD but did not predict its course. Combat exposure predicted PTSD course more strongly than any other risk factor. Findings suggest recovery from PTSD is significantly influenced by perceived social support

Persisting Posttraumatic Stress Disorder Symptoms and their Relationship to Functioning in Vietnam Veterans: A 14-Year Follow-Up

The authors examined the longitudinal association between persisting posttraumatic stress disorder (PTSD) symptoms and multiple domains of life functioning in a community sample of 1,377 American Legionnaire Vietnam veterans first assessed in 1984 and followed-up 14 years later. Almost 30 years after their return from Vietnam, 10% of veterans continued to experience severe PTSD symptoms. At all levels of combat exposure, persisting severe PTSD symptoms were associated with worse family relationships, more smoking, less life satisfaction and happiness, more mental health service use, and more nonspecific health complaints at the 14-year follow-up. Further investigation is needed to determine whether the PTSD-functioning relationship is causal and if successful treatment of PTSD is associated with improvement in functioning

Association of sexual harassment and sexual assault with midlife women’s mental and physical health

Importance: Sexual harassment and sexual assault are prevalent experiences among women. However, their association with health indices is less well understood. Objective: To investigate the association of history of sexual harassment and sexual assault with blood pressure, mood, anxiety, and sleep among midlife women. Design, setting, and participants: Nonsmoking women without cardiovascular disease were recruited from the community to undergo physical measurements (blood pressure, height, weight), medical history, and questionnaire psychosocial assessments (workplace sexual harassment, sexual assault, depression, anxiety, sleep). Exposures: Sexual harassment and sexual assault. Main outcomes and measures: Blood pressure, depressive symptoms, anxiety, and sleep characteristics. Results: Among the 304 nonsmoking women aged 40 to 60 years who participated in the study, all were free of clinical cardiovascular disease, and the mean (SD) age was 54.05 (3.99) years. A total of 19% reported a history of workplace sexual harassment (n = 58), and 22% reported a history of sexual assault (n = 67). Sexual harassment was related to significantly greater odds of stage 1 or 2 hypertension among women not taking antihypertensives (odds ratio [OR], 2.36; 95% CI, 1.10-5.06; P = .03) as well as clinically poor sleep (OR, 1.89; 95% CI, 1.05-3.42; P = .03), after adjusting for covariates. Sexual assault was associated with significantly greater odds of clinically elevated depressive symptoms (OR, 2.86; 95% CI, 1.42-5.77; multivariable P = .003), clinically relevant anxiety (OR, 2.26; 95% CI, 1.26-4.06; P = .006), and clinically poor sleep (OR, 2.15; 95% CI, 1.23-3.77; multivariable P = .007), after adjusting for covariates. Conclusions and relevance: Sexual harassment and sexual assault are prevalent experiences among midlife women. Sexual harassment was associated with higher blood pressure and poorer sleep. Sexual assault was associated with poorer mental health and sleep. Efforts to improve women's health should target sexual harassment and assault prevention

Caregiving and 5-HTTLPR Genotype Predict Adolescent Physiological Stress Reactivity: Confirmatory Tests of Gene × Environment Interactions

A theory-driven confirmatory approach comparing diathesis–stress and differential susceptibility models of Gene × Environment (G × E) interactions was applied to examine whether 5-HTTLPR genotype moderated the effect of early maternal caregiving on autonomic nervous system (ANS) stress reactivity in 113 adolescents aged 13–17 years. Findings supported a differential susceptibility, rather than diathesis–stress, framework. Carriers of one or more 5-HTTLPR short alleles (SS/SL carriers) reporting higher quality caregiving exhibited approach ANS responses to a speech task, whereas those reporting lower quality caregiving exhibited withdrawal ANS responses. Carriers of two 5-HTTLPR long alleles (LL carriers) were unaffected by caregiving. Findings suggest that 5-HTTLPR genotype and early caregiving in interaction are associated with ANS stress reactivity in adolescents in a “for better and for worse” fashion, and they demonstrate the promise of confirmatory methods for testing G × E interactions