Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume

Yuanchao Zheng, Melanie E. Garrett, Delin Sun, Emily K. Clarke-Rubright, Courtney C. Haswell, Adam X. Maihofer, Jeremy A. Elman, Carol E. Franz, Michael J. Lyons, William S. Kremen, Matthew Peverill, Kelly Sambrook, Katie A. McLaughlin, Nicholas D. Davenport, Seth Disner, Scott R. Sponheim, Elpiniki Andrew, Mayuresh Korgaonkar, Richard Bryant, Tim VarkevisserElbert Geuze, Jonathan Coleman, Jean C. Beckham, Nathan A. Kimbrel, Danielle Sullivan, Mark Miller, Jasmeet Hayes, Mieke Verfaellie, Erika Wolf, David Salat, Jeffrey M. Spielberg, William Milberg, Regina McGlinchey, Emily L. Dennis, Paul M. Thompson, Sarah Medland, Neda Jahanshad, Caroline M. Nievergelt, Allison E. Ashley-Koch, Mark W. Logue, Rajendra A. Morey

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10−20), thalamus (p = 7.46 × 10−10), caudate (p = 1.97 × 10−18), putamen (p = 1.7 × 10−12), and nucleus accumbens (p = 1.99 × 10−7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = −0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10−19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10−7) or PTSD (rs10861272; p = 1.78 × 10−6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.

Original languageEnglish (US)
Article number637
JournalTranslational psychiatry
Issue number1
StatePublished - Dec 2021

Bibliographical note

Funding Information:
We thank the National Institute for Mental Health Grant No. R01-MH111671-01 and VISN6 MIRECC (to RAM); VA Merit Grant Nos. 1I01RX000389-01 (to RAM) and 1I01CX000748-01A1 (to RAM); the National Institute of Neurological Disorders and Stroke Grant Nos. 5R01NS086885-02 and K23 MH073091-01 (to RAM); the Child Health Research Award (to KAM); the Charles H. Hood Foundation (to KAM); Young Investigator Grant, Brain, and Behavior Foundation, R01-MH103291 (to KAM); Traumatic Brain Injury National Network Research Center Grant No. B9254-C (to REM and WPM); National Health and Medical Research Council Program Grant 1073041 (to RB); R01-MH111671, R01MH117601, R01AG059874, MJFF 14848 (to NJ); VA RR&D I01RX000622; CDMRP W81XWH-08–2–0038 (to SRS); K99NS096116 (to ELD); VA RR&D 1K1RX002325; 1K2RX002922 (to SD); Department of Defense award number W81XWH-12-2-0012, ENIGMA was supported partly by NIH U54 EB020403 from the Big Data to Knowledge (BD2K) program, R56AG058854, R01MH116147, R01-MH111671, and P41 EB015922 (to PMT); NIMH R01MH106595 (to CMN). We thank all members of the respective site laboratories within the ENIGMA-PGC PTSD Working Group who contributed to general study organization, recruitment, data collection, and management, as well as subsequent analyses. We also thank the staff of all 16 cohorts across five countries for their help in neuroimaging and clinical data collection. Most importantly, we thank all of our study participants for their efforts to take part in this study. We thank Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind for ongoing support and building a collaborative scientific environment.

Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.


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