This CDA-2 application proposes a novel research project and rigorous training plan to provide Aliza Wingo, M.D., M.Sc. with a cutting-edge training in molecular genetics. Dr. Wingo proposes to perform a genome-wide association study (GWAS) of trauma-related resilience. Conceptually, resilience is resistance to adverse psychological sequelae despite exposure to stressful or traumatic experiences. It has a substantial genetic basis with heritability ranging from 38% to 71%, suggesting that genetic studies are likely to identify important causes of this trait. Her proposal has three specific aims. First, she will perform a GWAS of resilience in 8000 civilian subjects, whose phenotypes and genotypes are being gathered by the Grady Trauma Project, funded by NIMH and directed by her primary mentor. Resilience will be examined both as a dichotomous and quantitative phenotype. Next, she will replicate the significant findings from this GWAS in 950 veterans. It is her hypothesis that the resilient markers identified in the civilian population are also associated with resilience in the veteran population. Finally, she wil directly sequence the loci that are associated with resilience in at least 30 veterans to identify rare causal genetic variants of resilience. Results from this project will further our understandin of the genetic basis of resilience, which in turn informs efforts in enhancing protective factors o finding novel treatments or prevention strategies for major depression, PTSD, or substance use disorders, some of the most common and disabling trauma-related psychopathology in U.S. veterans. For training goals, Dr.
Wingo aims to acquire a strong foundation in population genetics, learn sophisticated analytical techniques for association mapping of complex phenotypes using genome-wide and imputation genotype data, and develop knowledge and expertise on next-generation sequencing study design and data analysis. To achieve these training goals, Dr. Wingo will attend courses on genetics and statistics, receive structured mentorship from her multidisciplinary mentoring team, and conduct the proposed project. Dr. Wingo has a strong multidisciplinary mentoring team, consisting of Kerry Ressler, M.D., Ph.D. (Molecular Biology, Genetics, Neuroscience, and Psychiatry), Bekh Bradley, Ph.D. (Psychology), Michael Epstein, Ph.D. (Statistical Genetics), and Timothy Read, Ph.D. (Human Genetics). The Human Genetics Department at Emory University, where most of Dr. Wingo's genetic training takes place, ranks in the top 10 genetic departments in the country and provides a strong training environment. Dr. Wingo's long-term goal is to capitalize on her multi-faceted understanding of psychiatric phenotypes as a psychiatrist, strong foundation in epidemiology and clinical research acquired through her Master of Science in Clinical Research, and the proposed cutting-edge genetic training to be a physician-scientist at the interface of psychiatry and genetics. She hopes to become an independent investigator and contribute to our understanding of the genetic basis of resilience and other psychiatric disorders.

Public Health Relevance

Exposure to combat trauma, childhood abuse, or other traumas substantially increases risk for major depression, post-traumatic stress disorder (PTSD), substance use disorders, or a combination of these disorders. Remarkably, some individuals suffer minimal or no adverse psychological sequelae despite prior trauma exposure, illustrating the concept of resilience. Resilience has a substantial genetic basis with heritability ranging from 38% to 71%, suggesting that genetic studies are likely to identify important causes of resilience. However, no gene for resilience has been confirmed thus far. Accordingly, the candidate proposes to perform the first genome-wide association study (GWAS) of resilience. This well-powered study will provide insight into genetic factors that underlie resilience and hence protect against trauma-related psychopathology that are common in U.S. veterans. In turn, knowledge of these genes is likely to lead to more effective prevention and treatment for common psychiatric disorders in veterans exposed to combat trauma.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Mental Health and Behavioral Science A (MHBA)
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Veterans Health Administration
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Breen, Michael S; Wingo, Aliza P; Koen, Nastassja et al. (2018) Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes. Brain Behav Immun 73:320-330
Lin, Cliff; Michopoulos, Vasiliki; Powers, Abigail et al. (2018) Affect, inflammation, and health in urban at-risk civilians. J Psychiatr Res 104:24-31
Wingo, Aliza P; Velasco, Eric R; Florido, Antonio et al. (2018) Expression of the PPM1F Gene Is Regulated by Stress and Associated With Anxiety and Depression. Biol Psychiatry 83:284-295
Berg, Carla J; Haardörfer, Regine; McBride, Colleen M et al. (2017) Resilience and biomarkers of health risk in Black smokers and nonsmokers. Health Psychol 36:1047-1058
Wingo, A P; Almli, L M; Stevens, J S et al. (2017) Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs. Mol Psychiatry 22:774-783
Kilaru, V; Iyer, S V; Almli, L M et al. (2016) Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder. Transl Psychiatry 6:e820
Niu, Ya-Nan; Zhu, Xinyi; Li, Juan et al. (2016) The ERP Effects of Combined Cognitive Training on Intention-Based and Stimulus-Based Actions in Older Chinese Adults. Front Psychol 7:1670
Nylocks, K M; Michopoulos, V; Rothbaum, A O et al. (2015) An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms. Am J Med Genet B Neuropsychiatr Genet 168B:307-15
Wingo, Aliza P; Baldessarini, Ross J; Windle, Michael (2015) Coping styles: longitudinal development from ages 17 to 33 and associations with psychiatric disorders. Psychiatry Res 225:299-304
Wingo, Aliza P; Almli, Lynn M; Stevens, Jennifer S et al. (2015) DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nat Commun 6:10106

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