Multivariate genome-wide analysis of stress-related quantitative phenotypes |
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| Affiliation: | 1. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, the Netherlands;2. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, the Netherlands;3. Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, the Netherlands;4. Research Centre, Military Mental Healthcare, Ministry of Defense, Utrecht, the Netherlands;5. Department of Psychiatry, Amsterdam UMC (location VUmc) / GGZ InGeest, Amsterdam, the Netherlands;6. Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), Amsterdam, the Netherlands;7. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, the Netherlands;8. Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands;9. Arq Psychotrauma Expert Group, Diemen, the Netherlands;10. GGNet, Apeldoorn, the Netherlands;1. Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue Suite 2190 Detroit MI 48201, United States;2. Division of Endocrinology, School of Medicine, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, United States;3. Department of Pharmaceutical Science, Wayne State University, United States;4. Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany;5. Technische Universität Dresden, Neuroimaging Center, Dresden, Germany;6. Zurich Center for Neuroeconomics, Department of Economics, University of Zurich, Zurich, Switzerland;7. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA;8. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA;1. Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, United States;2. Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville, TN, United States;3. Department of Psychology, Vanderbilt University, Nashville, TN, United States;4. Department of Psychology, The University of Tulsa, Tulsa, OK, United States;5. Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States;6. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States;7. Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States;8. Center for Behavioral Health Research, University of Tennessee, Knoxville, TN, United States |
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| Abstract: | Exposure to traumatic stress increases the odds of developing a broad range of psychiatric conditions. Genetic studies targeting multiple stress-related quantitative phenotypes may shed light on mechanisms underlying vulnerability to psychopathology in the aftermath of stressful events. We applied a multivariate genome-wide association study (GWAS) to a unique military cohort (N = 583) in which we measured biochemical and behavioral phenotypes. The availability of pre- and post-deployment measurements allowed to capture changes in these phenotypes in response to stress. For genome-wide significant loci, we performed functional annotation, phenome-wide analysis and quasi-replication in PTSD case-control GWASs. We discovered one genetic variant reaching genome-wide significant association, surviving permutation and sensitivity analyses (rs10100651, p = 9.9 × 10−9). Functional annotation prioritized the genes INTS8 and TP53INP1. A phenome-wide scan revealed a significant association of these same genes with sleeping problems, hypertension and subjective well-being. Finally, a targeted lookup revealed nominally significant association of rs10100651 in a PTSD case-control GWAS in the UK Biobank (p = 0.02). We provide comprehensive evidence from multiple resources hinting at a role of the highlighted genetic variant in the human stress response, marking the power of multivariate genome-wide analysis of quantitative measures in stress research. Future genetic and functional studies can target this locus to further assess its effects on stress mediation and its possible role in psychopathology or resilience. |
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