Prospective Study of Polygenic Risk, Protective Factors, and Incident Depression Following Combat Deployment in US Army Soldiers

Choi, Karmel W.; Chen, Chia‐Yen; Ursano, Robert J.; Sun, Xiaoying; Jain, Sonia; Kessler, Ronald C.; Wang, Min‐Jung; Wynn, Gary H.; Campbell‐Sills, Laura; Stein, Murray B.; Smoller, Jordan W.

doi:10.1101/361725

Cited by 5 publications

(4 citation statements)

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“…Previous work has shown that polygenic risk for depression is associated with depression symptom trajectories across time and also separately with the risk of depression after stressful life events . However, to our knowledge, no published research has examined polygenic influences on depression symptom trajectories following exposure to stressful life events.…”

Section: Discussionmentioning

confidence: 99%

Discriminating Heterogeneous Trajectories of Resilience and Depression After Major Life Stressors Using Polygenic Scores

et al. 2021

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IMPORTANCEMajor life stressors, such as loss and trauma, increase the risk of depression. It is known that individuals show heterogeneous trajectories of depressive symptoms following major life stressors, including chronic depression, recovery, and resilience. Although common genetic variation has been associated with depression risk, genomic factors that could help discriminate trajectories of risk vs resilience following adversity have not been identified. OBJECTIVE To assess the discriminatory accuracy of a deep neural net combining joint information from 21 psychiatric and health-related multiple polygenic scores (PGSs) for discriminating resilience vs other longitudinal symptom trajectories with use of longitudinal, genetically informed data on adults exposed to major life stressors. DESIGN, SETTING, AND PARTICIPANTSThe Health and Retirement Study is a longitudinal panel cohort study in US citizens older than 50 years, with data being collected once every 2 years between 1992 and 2010. A total of 2071 participants who were of European ancestry with available depressive symptom trajectory information after experiencing an index depressogenic major life stressor were included. Latent growth mixture modeling identified heterogeneous trajectories of depressive symptoms before and after major life stressors, including stable low symptoms (ie, resilience), as well as improving, emergent, and preexisting/chronic symptom patterns. Twenty-one PGSs were examined as factors distinctively associated with these heterogeneous trajectories. Local interpretable model-agnostic explanations were applied to examine PGSs associated with each trajectory. Data were analyzed using the DNN model from June to July 2020.EXPOSURES Development of depression and resilience were examined in older adults after a major life stressor, such as bereavement, divorce, and job loss, or major health events, such as myocardial infarction and cancer.MAIN OUTCOMES AND MEASURES Discriminatory accuracy of a deep neural net model trained for the multinomial classification of 4 distinct trajectories of depressive symptoms (Center for Epidemiologic Studies-Depression scale) based on 21 PGSs using supervised machine learning. RESULTSOf the 2071 participants, 1329 were women (64.2%); mean (SD) age was 55.96 (8.52) years. Of these, 1638 (79.1%) were classified as resilient, 160 (7.75) in recovery (improving), 159 (7.7%) with emerging depression, and 114 (5.5%) with preexisting/chronic depression symptoms. Deep neural nets distinguished these 4 trajectories with high discriminatory accuracy (multiclass micro-average area under the curve, 0.88; 95% CI, 0.87-0.89; multiclass macro-average area under the curve, 0.86; 95% CI, 0.85-0.87). Discriminatory accuracy was highest for preexisting/chronic depression (AUC 0.93), followed by emerging depression (AUC 0.88), recovery (AUC 0.87), resilience (AUC 0.75). CONCLUSIONS AND RELEVANCEThe results of the longitudinal cohort study suggest that multivariate PGS profiles provide information to accurately distinguish bet...

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Section: Discussionmentioning

confidence: 99%

Discriminating Heterogeneous Trajectories of Resilience and Depression After Major Life Stressors Using Polygenic Scores

et al. 2021

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“…Polygenic risk scores were approximately normally distributed across individuals ( Figure S3B). As in prior studies (Choi et al, 2018;Khera et al, 2016), we divided the sample into three groups of relative polygenic risk: low (quintile 1; N = 1,594), intermediate (quintiles 2-4; N = 4,781), and high (quintile 5; N = 1,593). As expected, these polygenic risk groups showed a dose-response relationship with incident depression ( Figure S3C), with individuals at high polygenic risk showing highest odds for developing depression (OR = 1.50, 95% CI = 1.16-1.94, p = .002), followed by those with intermediate polygenic risk (OR = 1.11, 95% CI = 0.89-1.39, p = .38), compared with those at low polygenic risk.…”

Section: Polygenic Risk Scoringmentioning

confidence: 99%

Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study

et al. 2019

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Background: Physical activity is increasingly recognized as an important modifiable factor for depression. However, the extent to which individuals with stable risk factors for depression, such as high genetic vulnerability, can benefit from the protective effects of physical activity, remains unknown. Using a longitudinal biobank cohort integrating genomic data from 7,968 individuals of European ancestry with high-dimensional electronic health records and lifestyle survey responses, we examined whether physical activity was prospectively associated with reduced risk for incident depression in the context of genetic vulnerability.Methods: We identified individuals with incident episodes of depression, based on two or more diagnostic billing codes for a depressive disorder within 2 years following their lifestyle survey, and no such codes in the year prior. Polygenic risk scores were derived based on large-scale genome-wide association results for major depression. We tested main effects of physical activity and polygenic risk scores on incident depression, and effects of physical activity within stratified groups of polygenic risk.Results: Polygenic risk was associated with increased odds of incident depression, and physical activity showed a protective effect of similar but opposite magnitude, even after adjusting for BMI, employment status, educational attainment, and prior depression. Higher levels of physical activity were associated with reduced odds of incident depression across all levels of genetic vulnerability, even among individuals at highest polygenic risk.Conclusions: Real-world data from a large healthcare system suggest that individuals with high genetic vulnerability are more likely to avoid incident episodes of depression if they are physically active.

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“…In the realm of psychiatry, studies have begun to adopt this approach. In a prospective cohort of US Army soldiers (N=3,900), we found that unit cohesion-support and respect between peers and with group leaders-was associated with reduced risk for new-onset depression even for individuals with high polygenic risk for depression (67). Another study in a population-based cohort (N=4,166) found that personal coping abilities (indexed by selfreported trait resilience) attenuated associations between polygenic risk for depression and actual depression, even when adjusting for vulnerability factors like neuroticism (68).…”

Section: Genetic and Environmental Factors That Contribute To Resilience Processesmentioning

confidence: 87%

Genomics and psychological resilience: a research agenda

et al. 2019

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Although exposure to adversity increases risk for poor mental health outcomes, many people exposed to adversity do not develop such outcomes. Psychological resilience, defined broadly as positive emotional and/or behavioral adaptation to adversity, may be influenced by genetic factors that have remained largely unexplored in the era of large-scale genome-wide studies. In this Perspective, we provide an integrative framework for studying human genome-wide variation underlying resilience. We first outline three complementary working definitions of psychological resilience-as a capacity, process, and outcome. For each definition, we review emerging empirical evidence, including findings from positive psychology, to illustrate how a resiliencebased framework can guide novel and fruitful directions for the field of psychiatric genomics, distinct from ongoing study of psychiatric risk and related traits. Finally, we provide practical recommendations for future genomic research on resilience, highlighting a need to augment crosssectional findings with prospective designs that include detailed measurement of adversities and outcomes. A research framework that explicitly addresses resilience could help us to probe biological mechanisms of stress adaptation, identify individuals who may benefit most from prevention and early intervention, and ascertain modifiable protective factors that mitigate negative outcomes even for those at high genetic risk.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Prospective Study of Polygenic Risk, Protective Factors, and Incident Depression Following Combat Deployment in US Army Soldiers

Abstract: Background: Whereas genetic susceptibility increases risk for major depressive disorder

Cited by 5 publications

References 40 publications

Discriminating Heterogeneous Trajectories of Resilience and Depression After Major Life Stressors Using Polygenic Scores

Discriminating Heterogeneous Trajectories of Resilience and Depression After Major Life Stressors Using Polygenic Scores

Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study

Genomics and psychological resilience: a research agenda

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