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ABSTRACT A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results

have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of,

PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working

group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics

across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18–83, 92% of whom were trauma-exposed, we report associations between PTSD and

disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen’s _d_ = −0.11, _p_ = 0.0055). The tapetum connects the

left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially

confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications.

Our results show that PTSD may be associated with alterations in the broader hippocampal network. Access through your institution Buy or subscribe This is a preview of subscription content,

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SEX-RELATED ABNORMALITIES IN STRUCTURAL CONNECTIVITY Article 20 July 2021 CORTICAL VOLUME ABNORMALITIES IN POSTTRAUMATIC STRESS DISORDER: AN ENIGMA-PSYCHIATRIC GENOMICS CONSORTIUM PTSD

WORKGROUP MEGA-ANALYSIS Article 07 December 2020 PROGNOSTIC NEUROIMAGING BIOMARKERS OF TRAUMA-RELATED PSYCHOPATHOLOGY: RESTING-STATE FMRI SHORTLY AFTER TRAUMA PREDICTS FUTURE PTSD AND

DEPRESSION SYMPTOMS IN THE AURORA STUDY Article 21 January 2021 CODE AVAILABILITY All analyses were conducted using generalizable scripts available on the ENIGMA-GitHub

https://github.com/ENIGMA-git/ENIGMA/tree/master/WorkingGroups/EffectSize_and_GLM. Individual ROI level data were shared with the central site and processed using a set of R scripts with

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2017;174:60–69. Article  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS K99NS096116 to ELD; CIHR, CIMVHR; Dana Foundation (to JBN); the University of Wisconsin Institute for

Clinical and Translational Research (to Dr Emma Seppala); a National Science Foundation Graduate Research Fellowship (to DWG); R01MH043454 and T32MH018931 (to RJD); and a core grant to the

Waisman Center from the National Institute of Child Health and Human Development (P30HD003352); Defense and Veterans Brain Injury Centers, the U.S. Army Medical Research and Materiel Command

(USAMRMC; W81XWH-13-2-0025) and the Chronic Effects of Neurotrauma Consortium (CENC; PT108802-SC104835); Department of Defense award number W81XWH-12-2-0012; ENIGMA was also supported in

part by NIH U54EB020403 from the Big Data to Knowledge (BD2K) program, R56AG058854, R01MH116147, R01MH111671, and P41EB015922; Department of Veterans Affairs via support for the National

Center for PTSD, NIAAA via its support for (P50) Center for the Translational Neuroscience if Alcohol, and NCATS via its support of (CTSA) Yale Center for Clinical Investigation; DoD

W81XWH-10-1-0925; Center for Brain and Behavior Research Pilot Grant; South Dakota Governor’s Research Center Grant; F32MH109274; Funding from the Bill & Melinda Gates Foundation;

Funding from the SAMRC Unit on Risk & Resilience in Mental Disorders; German Research Foundation grant to JKD (numbers DA 1222/4-1 and WA 1539/8-2).; German Research Society (Deutsche

Forschungsgemeinschaft, DFG; SFB/TRR 58: C06, C07); I01-CX000715 & I01-CX001542; K01MH118428; K23MH090366; K2CX001772, Clinical Science Research and Development Service, VA Office of

Research and Development; MH098212; MH071537; M01RR00039; UL1TR000454; HD071982; HD085850; MH101380; NARSAD 27040; NARSAD Young Investigator, K01MH109836, Young Investigator Grant, Korean

Scientists and Engineers Association; NHMRC Program Grant # 1073041; R01AG050595, R01AG022381; R01AG058822; R01EB015611; R01MH105355; R01MH105355, R01DA035484; R01MH111671, R01MH117601,

R01AG059874, MJFF 14848; R01MH111671; VISN6 MIRECC; R21MH112956, Anonymous Women's Health Fund, Kasparian Fund, Trauma Scholars Fund, Barlow Family Fund; South African Medical Research

Council for the “Shared Roots” Flagship Project, Grant no. MRC-RFA-IFSP-01-2013/SHARED ROOTS” through funding received from the South African National Treasury under its Economic

Competitiveness and Support Package. The work by LLvdH reported herein was made possible through funding by the South African Medical Research Council through its Division of Research

Capacity Development under the SAMRC CLINICIAN RESEARCHER (M.D PHD) SCHOLARSHIP PROGRAMME from funding received from the South African National Treasury.; South African Research Chairs

Initiative in Posttraumatic Stress Disorder through the Department of Science and Technology and the National Research Foundation.; the National Natural Science Foundation of China (No.

31271099, 31471004), the Key Research Program of the Chinese Academy of Sciences (No. ZDRW-XH-2019-4); The study was supported by ZonMw, the Netherlands organization for Health Research and

Development (40-00812-98-10041), and by a grant from the Academic Medical Center Research Council (110614) both awarded to MO.; Translational Research Center for TBI and Stress Disorders

(TRACTS), a VA Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence (B9254-C) at VA Boston Healthcare System.; VA CSR&D 1IK2CX001680; VISN17

Center of Excellence Pilot funding; VA CSR&D 822-MR-18176 and Senior Career Scientist Award; VA National Center for PTSD; VA RR&D 1IK2RX000709; VA RR&D 1K1RX002325; 1K2RX002922;

VA RR&D I01RX000622; CDMRP W81XWH-08–2–0038; W81XWH08-2-0159 (PI: MBS) from the US Department of Defense. The views reflected here are strictly those of the authors and do not constitute

endorsement by any of the funding sources listed here. AUTHOR INFORMATION Author notes * These authors contributed equally: Neda Jahanshad, Rajendra A. Morey AUTHORS AND AFFILIATIONS *

Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA Emily L. Dennis, Sinead Kelly, Philipp Kinzel, Inga Koerte & Martha Shenton *

Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, CA, USA Emily L. Dennis, Lauren E. Salminen, Paul M. Thompson &

 Neda Jahanshad * Department of Neurology, University of Utah, Salt Lake City, UT, USA Emily L. Dennis, Carmen Velez, Benjamin S. C. Wade, David F. Tate & Elisabeth A. Wilde * Stanford

Neurodevelopment, Affect, and Psychopathology Laboratory, Stanford, CA, USA Emily L. Dennis * Minneapolis VA Health Care System, Minneapolis, MN, USA Seth G. Disner, Nicholas D. Davenport 

& Scott R. Sponheim * Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA Seth G. Disner, Nicholas D. Davenport & Scott R. Sponheim * Department of Psychiatry and

Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA Negar Fani, Tanja Jovanovic, Kerry J. Ressler, Jennifer Stevens & Sanne J. H. van Rooij * National Center for

PTSD, VA Boston Healthcare System, Boston, MA, USA Mark Logue & Danielle R. Sullivan * Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA Mark Logue, 

Danielle R. Sullivan & Mieke Verfaellie * Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA Mark Logue * Department of Biostatistics, Boston University School of

Public Health, Boston, MA, USA Mark Logue * Brain Imaging and Analysis Center, Duke University, Durham, NC, USA Emily K. Clarke, Courtney C. Haswell & Rajendra A. Morey * VISN 6 MIRECC,

Durham VA, Durham, NC, USA Emily K. Clarke, Courtney C. Haswell & Rajendra A. Morey * Clinical Neuroscience Division, National Center for PTSD; Department of Psychiatry, Yale University

School of Medicine, New Haven, CT, USA Christopher L. Averill, John Krystal & Chadi G. Abdallah * Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South

Dakota, Vermillion, SD, USA Lee A. Baugh, Gina L. Forster & Kelene A Fercho * Center for Brain and Behavior Research, University of South Dakota, Vermillion, SD, USA Lee A. Baugh, Gina

L. Forster, Raluca M. Simons & Kelene A Fercho * Sioux Falls VA Health Care System, Sioux Falls, SD, USA Lee A. Baugh, Jeffrey S. Simons & Kelene A Fercho * Center of Excellence for

Stress and Mental Health, VA San Diego Healthcare System, La Jolla, CA, USA Jessica Bomyea, Alan Simmons & William S. Kremen * Department of Psychiatry, University of California, San

Diego, La Jolla, CA, USA Jessica Bomyea, Alan Simmons, Carol Franz, William S. Kremen & Murray B. Stein * Department of Psychological Sciences, Center for Trauma Recovery University of

Missouri-St. Louis, St. Louis, MO, USA Steven E. Bruce * Department of Psychiatry, Columbia University Medical Center, New York, NY, USA Jiook Cha, Benjamin Suarez-Jimenez, Xi Zhu & 

Yuval Neria * New York State Psychiatric Institute, New York, NY, USA Jiook Cha, Benjamin Suarez-Jimenez, Xi Zhu & Yuval Neria * Health Services Research Center, University of

California, San Diego, CA, USA Kyle Choi * Department of Psychiatry, Western University, London, ON, Canada Maria Densmore, Richard W. J. Neufeld, Jean Théberge & Ruth A Lanius * Imaging

Division, Lawson Health Research Institute, London, ON, Canada Maria Densmore, Jean Théberge & Ruth A Lanius * Department of Psychiatry, Stellenbosch University, Stellenbosch, South

Africa Stefan du Plessis & Leigh van den Heuvel * Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, 9054, New Zealand Gina L. Forster * Department of

Psychiatry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Jessie L. Frijling, Saskia B.

J. Koch, Laura Nawijn, Mirjam van Zuiden & Miranda Olff * Cognitive and Clinical Neuroimaging Core, McLean Hospital, Belmont, MA, USA Atilla Gonenc & Staci Gruber * Department of

Psychiatry, Harvard Medical School, Boston, MA, USA Atilla Gonenc, Staci Gruber, Lauren A. M. Lebois, Kerry J. Ressler, Sherry Winternitz, Milissa L Kaufman, Regina McGlinchey & William

Milberg * Center for Healthy Minds, University of Wisconsin-Madison, Madison, WI, USA Daniel W. Grupe & Richard J Davidson * Division of Neuroradiology, Brigham and Women’s Hospital,

Boston, MA, USA Jeffrey P. Guenette * Department of Psychology, The Ohio State University, Columbus, OH, USA Jasmeet Hayes * Institute of Medical Psychology and Systems Neuroscience,

University of Münster, Münster, Germany David Hofmann & Thomas Straube * SA Medical Research Council Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry &

Neuroscience Institute, University of Cape Town, Cape Town, South Africa Jonathan Ipser, Sheri Koopowitz & Dan J. Stein * Department of Psychiatry and Behavioral Neuroscience, Wayne

State University School of Medicine, Detroit, MI, USA Tanja Jovanovic * Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Sinead Kelly *

Brain Center Rudolf Magnus, Department of Psychiatry, UMCU, Utrecht, The Netherlands Mitzy Kennis & Elbert Geuze * Brain Research and Innovation Centre, Ministry of Defence, Utrecht,

The Netherlands Mitzy Kennis & Elbert Geuze * Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Ludwig-Maximilians-Universität,

Munich, Germany Philipp Kinzel & Inga Koerte * Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, The

Netherlands Saskia B. J. Koch & Kerry J. Ressler * Brain Dynamics Centre, Westmead Institute of Medical Research, University of Sydney, Westmead, NSW, Australia Mayuresh Korgaonkar *

Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA Lauren A. M. Lebois & Jonathan Wolff * Laboratory for Traumatic Stress Studies, CAS Key Laboratory of

Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China Gen Li, Ye Zhu & Li. Wang * Department of Psychology, University of Chinese Academy of Sciences,

Beijing, China Gen Li, Ye Zhu & Li. Wang * Departments of Radiology, Psychiatry, and Biomedical Engineering, University of Iowa, Iowa City, IA, USA Vincent A. Magnotta * University

Medical Centre Charite, Berlin, Germany Antje Manthey, Anika Sierk & Henrik Walter * VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, USA Geoff J. May, 

Steven M. Nelson & Evan M Gordon * Department of Psychology and Neuroscience, Baylor University, Waco, TX, USA Geoff J. May, Steven M. Nelson & Evan M Gordon * Department of

Psychiatry and Behavioral Science, Texas A&M Health Science Center, Bryan, TX, USA Geoff J. May * Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas

at Dallas, Dallas, TX, USA Geoff J. May, Steven M. Nelson & Evan M Gordon * Menninger Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA Deleene S. Menefee * South

Central MIRECC, Houston, TX, USA Deleene S. Menefee * Department of Psychiatry, Amsterdam University Medical Centers, Location VU University Medical Center, VU University, Amsterdam, The

Netherlands Laura Nawijn & Dick J. Veltman * Department of Psychology, Western University, London, ON, Canada Richard W. J. Neufeld * Department of Neuroscience, Western University,

London, ON, Canada Richard W. J. Neufeld & Ruth A Lanius * Department of Psychology, University of British Columbia, Okanagan, BC, Canada Richard W. J. Neufeld * Department of

Psychiatry, University of Wisconsin-Madison, Madison, WI, USA Jack B. Nitschke & Richard J Davidson * University of the Sunshine Coast, Birtinya, QLD, Australia Daniel O’Doherty & 

Jim Lagopoulos * Department of Psychology, University of Washington, Seattle, WA, USA Matthew Peverill * South African Medical Research Council / Stellenbosch University Genomics of Brain

Disorders Research Unit, Department of Psychiatry, Stellenbosch University, Cape Town, South Africa Annerine Roos & Soraya Seedat * Department of Psychology and Brain Sciences,

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Margaret A. Sheridan * Department of Psychology, University of South Dakota, Vermillion, SD, USA Raluca M. Simons & 

Jeffrey S. Simons * Department of Medical Biophysics, Western University, London, ON, Canada Jean Théberge * Houston Fire Department, Houston, TX, USA Jana K. Tran * Department of

Psychiatry, LUMC, Leiden, The Netherlands Steven J. A. van der Werff, Robert R. J. M. Vermeiren & Nic J. A. van der Wee * Leiden Institute for Brain and Cognition, Leiden, The

Netherlands Steven J. A. van der Werff & Nic J. A. van der Wee * Missouri Institute of Mental Health and University of Missouri, St Louis, MO, USA Carmen Velez, Benjamin S. C. Wade &

 David F. Tate * Memory Disorders Research Center, VA Boston Healthcare System, Boston, MA, USA Mieke Verfaellie * Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University

of California, Los Angeles, Los Angeles, CA, USA Benjamin S. C. Wade * Dartmouth College, Hanover, NH, USA Tor Wager * Division of Women’s Mental Health, McLean Hospital, Belmont, MA, USA

Sherry Winternitz & Milissa L Kaufman * Joint Trauma System, 3698 Chambers Pass, Joint Base San Antonio, Fort Sam Houston, TX, USA Gerald York * Alaska Radiology Associates, Anchorage,

AK, USA Gerald York * School of Psychology, University of New South Wales, Sydney, NSW, Australia Richard Bryant * Department of Clinical Psychology, University of Groningen, Groningen, The

Netherlands Judith K Daniels * Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA Richard J Davidson * Civil Aerospace Medical Institute, US Federal Aviation

Administration, Oklahoma City, OK, USA Kelene A Fercho * Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA Carol Franz & William S. Kremen *

Dept. of Psychological & Brain Sciences, Boston University, Boston, MA, USA Michael J. Lyons * Departments of Neurology and Pediatrics, Baylor College of Medicine, Houston, TX, USA

Stephen R McCauley * H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, USA Stephen R McCauley & Elisabeth A. Wilde * Geriatric

Research Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, MA, USA Regina McGlinchey * Department of

Psychology, Harvard University, Cambridge, MA, USA Katie A. McLaughlin * ARQ National Psychotrauma Centre, Diemen, The Netherlands William Milberg & Miranda Olff * VA Boston Healthcare

System, Brockton Division, Brockton, MA, USA Martha Shenton * Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA Murray B. Stein * George

E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, USA Elisabeth A. Wilde * Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA

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CONTRIBUTIONS ELD, SGD, NF, LES, ML, EKC, NJ, and RAM wrote the initial draft, all authors reviewed and edited the manuscript. All authors contributed data to the analyses. CORRESPONDING

AUTHOR Correspondence to Emily L. Dennis. ETHICS DECLARATIONS CONFLICT OF INTEREST CGA has served as a consultant, speaker and/or on advisory boards for FSV7, Lundbeck, Genentech and

Janssen, and editor of Chronic Stress for Sage Publications, Inc.; he has filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). RJD

is the founder and president of, and serves on the board of directors for, the nonprofit organization Healthy Minds Innovations, Inc. JK is a consultant for AbbVie, Inc., Amgen, Astellas

Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM

Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc.,

and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven

Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, US Patent No.

5,447,948 (issued September 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued July 15, 2014); and filed a patent for

Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on March 5, 2014); US application or Patent Cooperation Treaty international application No.

14/306,382 (filed on June 17, 2014). Filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). NJ received partial research support from

Biogen, Inc. (Boston, USA) for research unrelated to the content of this paper. PMT received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of

this paper. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY

INFORMATION SUPPLEMENTAL MATERIAL RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Dennis, E.L., Disner, S.G., Fani, N. _et al._ Altered white matter

microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium. _Mol Psychiatry_ 26, 4315–4330 (2021).

https://doi.org/10.1038/s41380-019-0631-x Download citation * Received: 20 June 2019 * Revised: 20 November 2019 * Accepted: 02 December 2019 * Published: 19 December 2019 * Issue Date:

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