Rare copy number variation in posttraumatic stress disorder

Adam X Maihofer^{1

2

3}, Worrawat Engchuan^{4

5}, Guillaume Huguet⁶, Marieke Klein⁷, Jeffrey R MacDonald⁴, Omar Shanta⁸, Bhooma Thiruvahindrapuram⁴, Martineau Jean-Louis⁹, Zohra Saci⁶, Sebastien Jacquemont^{6

10

11}, Stephen W Scherer^{4

12

13}, Elizabeth Ketema^{7

14

15}, Allison E Aiello¹⁶, Ananda B Amstadter¹⁷, Esmina Avdibegović¹⁸, Dragan Babic¹⁹, Dewleen G Baker^{7

14

20}, Jonathan I Bisson²¹, Marco P Boks²², Elizabeth A Bolger^{23

24}, Richard A Bryant²⁵, Angela C Bustamante²⁶, Jose Miguel Caldas-de-Almeida²⁷, Graça Cardoso²⁸, Jurgen Deckert²⁹, Douglas L Delahanty^{30

31}, Katharina Domschke^{32

33}, Boadie W Dunlop³⁴, Alma Dzubur-Kulenovic³⁵, Alexandra Evans²¹, Norah C Feeny³⁶, Carol E Franz⁷, Aarti Gautam³⁷, Elbert Geuze^{38

39}, Aferdita Goci⁴⁰, Rasha Hammamieh³⁷, Miro Jakovljevic⁴¹, Marti Jett^{42

43}, Ian Jones²¹, Milissa L Kaufman^{23

24}, Ronald C Kessler⁴⁴, Anthony P King⁴⁵, William S Kremen⁷, Bruce R Lawford⁴⁶, Lauren A M Lebois^{23

24}, Catrin Lewis²¹, Israel Liberzon⁴⁷, Sarah D Linnstaedt⁴⁸, Bozo Lugonja²¹, Jurjen J Luykx^{39

49}, Michael J Lyons⁵⁰, Matig R Mavissakalian⁵¹, Katie A McLaughlin⁵², Samuel A McLean^{48

53}, Divya Mehta^{46

54}, Rebecca Mellor⁵⁵, Charles Phillip Morris⁴⁶, Seid Muhie⁵⁶, Holly K Orcutt⁵⁷, Matthew Peverill⁵⁸, Andrew Ratanatharathorn^{59

60}, Victoria B Risbrough^{7

14

15}, Albert Rizzo⁶¹, Andrea L Roberts⁶², Alex O Rothbaum⁶³, Barbara O Rothbaum⁶⁴, Peter Roy-Byrne⁶⁵, Kenneth J Ruggiero⁶⁶, Bart P F Rutten⁶⁷, Dick Schijven^{39

49}, Julia S Seng^{68

69

70

71}, Christina M Sheerin¹⁷, Michael A Sorenson⁷, Martin H Teicher^{23

72}, Monica Uddin⁷³, Robert J Ursano⁷⁴, Christiaan H Vinkers^{75

76

77}, Joanne Voisey^{46

54}, Heike Weber²⁹, Sherry Winternitz^{23

24}, Miguel Xavier⁷⁸, Ruoting Yang⁵⁶, Ross McD Young^{79

80}, Lori A Zoellner⁶⁵; Psychiatric Genomics Consortium PTSD Working Group; Psychiatric Genomics Consortium CNV Working Group; Rany M Salem⁸¹, Richard A Shaffer⁸², Tianying Wu^{83

84}, Kerry J Ressler^{23

24

64}, Murray B Stein^{7

20

85}, Karestan C Koenen^{86

87

88}, Jonathan Sebat^#^{7

89

90}, Caroline M Nievergelt^#^{7

14

15}

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. amaihofer@health.ucsd.edu.
² Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. amaihofer@health.ucsd.edu.
³ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA. amaihofer@health.ucsd.edu.
⁴ The Hospital for Sick Children, Genetics and Genome Biology, Toronto, Ontario, Canada.
⁵ The Hospital for Sick Children, The Centre for Applied Genomics, Toronto, Ontario, Canada.
⁶ Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montreal, Quebec, Canada.
⁷ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁸ Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
⁹ Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montreal, Quebec, Canada.
¹⁰ Department of Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland.
¹¹ Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
¹² University of Toronto, McLaughlin Centre, Toronto, Ontario, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
¹⁵ Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
¹⁶ Department of Epidemiology, Robert N Butler Columbia Aging Center, Columbia University, New York, NY, USA.
¹⁷ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
¹⁸ Department of Psychiatry, University Clinical Center of Tuzla, Tuzla, Bosnia and Herzegovina.
¹⁹ Department of Psychiatry, University Clinical Center of Mostar, Mostar, Bosnia and Herzegovina.
²⁰ Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
²¹ MRC Centre for Psychiatric Genetics and Genomics, Cardiff University, National Centre for Mental Health, Cardiff, South Glamorgan, UK.
²² Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, the Netherlands.
²³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁴ McLean Hospital, Belmont, MA, USA.
²⁵ Department of Psychology, University of New South Wales, Sydney, NSW, Australia.
²⁶ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
²⁷ CEDOC-Chronic Diseases Research Centre, Lisbon Institute of Global Mental Health, Lisbon, Portugal.
²⁸ Lisbon Institute of Global Mental Health and Comprehensive Health Research Centre, Universidade Nova de Lisboa, Lisboa, Portugal.
²⁹ University Hospital of Wuerzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, Wuerzburg, Germany.
³⁰ Department of Psychological Sciences, Kent State University, Kent, OH, USA.
³¹ Research and Sponsored Programs, Kent State University, Kent, OH, USA.
³² Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
³³ Faculty of Medicine, Centre for Basics in Neuromodulation, University of Freiburg, Freiburg, Germany.
³⁴ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
³⁵ Department of Psychiatry, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina.
³⁶ Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA.
³⁷ Walter Reed Army Institute of Research, Medical Readiness Systems Biology, Center for Military Psychiatry and Neuroscience, Silver Spring, MD, USA.
³⁸ Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, the Netherlands.
³⁹ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
⁴⁰ Department of Psychiatry, University Clinical Centre of Kosovo, Prishtina, Kosovo.
⁴¹ Department of Psychiatry, University Hospital Center of Zagreb, Zagreb, Croatia.
⁴² US Medical Research & Development Comm, Fort Detrick, MD, USA.
⁴³ Walter Reed Army Institute of Research, Headquarter, Silver Spring, MD, USA.
⁴⁴ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴⁵ Ohio State University, College of Medicine, Institute for Behavioral Medicine Research, Columbus, OH, USA.
⁴⁶ School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, Australia.
⁴⁷ Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA.
⁴⁸ Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁹ Department of Translational Neuroscience, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
⁵⁰ Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA.
⁵¹ Department of Psychiatry, University Hospitals, Cleveland, OH, USA.
⁵² Department of Psychology, Harvard University, Boston, MA, USA.
⁵³ Department of Emergency Medicine, UNC Institute for Trauma Recovery, Chapel Hill, NC, USA.
⁵⁴ Queensland University of Technology, Centre for Genomics and Personalised Health, Kelvin Grove, QLD, Australia.
⁵⁵ Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia.
⁵⁶ Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁵⁷ Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
⁵⁸ Department of Psychology, University of Washington, Seattle, WA, USA.
⁵⁹ Department of Epidemiology, Columbia University Mailmain School of Public Health, New York, NY, USA.
⁶⁰ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁶¹ University of Southern California, Institute for Creative Technologies, Los Angeles, CA, USA.
⁶² Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶³ Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
⁶⁴ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁶⁵ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
⁶⁶ Department of Nursing and Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
⁶⁷ Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Maastricht, Limburg, the Netherlands.
⁶⁸ University of Michigan, School of Nursing, Ann Arbor, MI, USA.
⁶⁹ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
⁷⁰ Department of Women's and Gender Studies, University of Michigan, Ann Arbor, MI, USA.
⁷¹ University of Michigan, Institute for Research on Women and Gender, Ann Arbor, MI, USA.
⁷² Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, USA.
⁷³ Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.
⁷⁴ Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA.
⁷⁵ Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands.
⁷⁶ Department of Psychiatry, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷⁷ Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷⁸ Universidade Nova de Lisboa, Nova Medical School, Lisboa, Portugal.
⁷⁹ Queensland University of Technology, School of Clinical Sciences, Kelvin Grove, QLD, Australia.
⁸⁰ University of the Sunshine Coast, The Chancellory, Sippy Downs, QLD, Australia.
⁸¹ University of California San Diego, Herbert Wertheim School of Public Health and Human Longevity Science, La Jolla, CA, USA.
⁸² Department of Epidemiology and Health Sciences, Naval Health Research Center, San Diego, CA, USA.
⁸³ Division of Epidemiology and Biostatistics, San Diego State University, School of Public Health, San Diego, CA, USA.
⁸⁴ University of California, San Diego, Moores Cancer Center, San Diego, CA, USA.
⁸⁵ University of California San Diego, School of Public Health, La Jolla, CA, USA.
⁸⁶ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
⁸⁷ Department of Epidemiology, Harvard T. H. School of Public Health, Boston, MA, USA.
⁸⁸ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
⁸⁹ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
⁹⁰ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.

^# Contributed equally.

PMID: 36131047
PMCID: PMC9763110
DOI: 10.1038/s41380-022-01776-4

Rare copy number variation in posttraumatic stress disorder

Adam X Maihofer et al. Mol Psychiatry. 2022 Dec.

. 2022 Dec;27(12):5062-5069.

doi: 10.1038/s41380-022-01776-4. Epub 2022 Sep 21.

Authors

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. amaihofer@health.ucsd.edu.
² Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. amaihofer@health.ucsd.edu.
³ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA. amaihofer@health.ucsd.edu.
⁴ The Hospital for Sick Children, Genetics and Genome Biology, Toronto, Ontario, Canada.
⁵ The Hospital for Sick Children, The Centre for Applied Genomics, Toronto, Ontario, Canada.
⁶ Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montreal, Quebec, Canada.
⁷ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁸ Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
⁹ Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montreal, Quebec, Canada.
¹⁰ Department of Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland.
¹¹ Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
¹² University of Toronto, McLaughlin Centre, Toronto, Ontario, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Veterans Affairs San Diego Healthcare System, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
¹⁵ Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
¹⁶ Department of Epidemiology, Robert N Butler Columbia Aging Center, Columbia University, New York, NY, USA.
¹⁷ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
¹⁸ Department of Psychiatry, University Clinical Center of Tuzla, Tuzla, Bosnia and Herzegovina.
¹⁹ Department of Psychiatry, University Clinical Center of Mostar, Mostar, Bosnia and Herzegovina.
²⁰ Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
²¹ MRC Centre for Psychiatric Genetics and Genomics, Cardiff University, National Centre for Mental Health, Cardiff, South Glamorgan, UK.
²² Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, the Netherlands.
²³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁴ McLean Hospital, Belmont, MA, USA.
²⁵ Department of Psychology, University of New South Wales, Sydney, NSW, Australia.
²⁶ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
²⁷ CEDOC-Chronic Diseases Research Centre, Lisbon Institute of Global Mental Health, Lisbon, Portugal.
²⁸ Lisbon Institute of Global Mental Health and Comprehensive Health Research Centre, Universidade Nova de Lisboa, Lisboa, Portugal.
²⁹ University Hospital of Wuerzburg, Center of Mental Health, Psychiatry, Psychosomatics and Psychotherapy, Wuerzburg, Germany.
³⁰ Department of Psychological Sciences, Kent State University, Kent, OH, USA.
³¹ Research and Sponsored Programs, Kent State University, Kent, OH, USA.
³² Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
³³ Faculty of Medicine, Centre for Basics in Neuromodulation, University of Freiburg, Freiburg, Germany.
³⁴ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
³⁵ Department of Psychiatry, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina.
³⁶ Department of Psychological Sciences, Case Western Reserve University, Cleveland, OH, USA.
³⁷ Walter Reed Army Institute of Research, Medical Readiness Systems Biology, Center for Military Psychiatry and Neuroscience, Silver Spring, MD, USA.
³⁸ Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, the Netherlands.
³⁹ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
⁴⁰ Department of Psychiatry, University Clinical Centre of Kosovo, Prishtina, Kosovo.
⁴¹ Department of Psychiatry, University Hospital Center of Zagreb, Zagreb, Croatia.
⁴² US Medical Research & Development Comm, Fort Detrick, MD, USA.
⁴³ Walter Reed Army Institute of Research, Headquarter, Silver Spring, MD, USA.
⁴⁴ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴⁵ Ohio State University, College of Medicine, Institute for Behavioral Medicine Research, Columbus, OH, USA.
⁴⁶ School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, Australia.
⁴⁷ Department of Psychiatry and Behavioral Sciences, Texas A&M University College of Medicine, Bryan, TX, USA.
⁴⁸ Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁹ Department of Translational Neuroscience, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
⁵⁰ Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA.
⁵¹ Department of Psychiatry, University Hospitals, Cleveland, OH, USA.
⁵² Department of Psychology, Harvard University, Boston, MA, USA.
⁵³ Department of Emergency Medicine, UNC Institute for Trauma Recovery, Chapel Hill, NC, USA.
⁵⁴ Queensland University of Technology, Centre for Genomics and Personalised Health, Kelvin Grove, QLD, Australia.
⁵⁵ Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia.
⁵⁶ Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁵⁷ Department of Psychology, Northern Illinois University, DeKalb, IL, USA.
⁵⁸ Department of Psychology, University of Washington, Seattle, WA, USA.
⁵⁹ Department of Epidemiology, Columbia University Mailmain School of Public Health, New York, NY, USA.
⁶⁰ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁶¹ University of Southern California, Institute for Creative Technologies, Los Angeles, CA, USA.
⁶² Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶³ Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
⁶⁴ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
⁶⁵ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
⁶⁶ Department of Nursing and Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
⁶⁷ Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, School for Mental Health and Neuroscience, Maastricht, Limburg, the Netherlands.
⁶⁸ University of Michigan, School of Nursing, Ann Arbor, MI, USA.
⁶⁹ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
⁷⁰ Department of Women's and Gender Studies, University of Michigan, Ann Arbor, MI, USA.
⁷¹ University of Michigan, Institute for Research on Women and Gender, Ann Arbor, MI, USA.
⁷² Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, USA.
⁷³ Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.
⁷⁴ Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA.
⁷⁵ Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands.
⁷⁶ Department of Psychiatry, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷⁷ Department of Anatomy and Neurosciences, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁷⁸ Universidade Nova de Lisboa, Nova Medical School, Lisboa, Portugal.
⁷⁹ Queensland University of Technology, School of Clinical Sciences, Kelvin Grove, QLD, Australia.
⁸⁰ University of the Sunshine Coast, The Chancellory, Sippy Downs, QLD, Australia.
⁸¹ University of California San Diego, Herbert Wertheim School of Public Health and Human Longevity Science, La Jolla, CA, USA.
⁸² Department of Epidemiology and Health Sciences, Naval Health Research Center, San Diego, CA, USA.
⁸³ Division of Epidemiology and Biostatistics, San Diego State University, School of Public Health, San Diego, CA, USA.
⁸⁴ University of California, San Diego, Moores Cancer Center, San Diego, CA, USA.
⁸⁵ University of California San Diego, School of Public Health, La Jolla, CA, USA.
⁸⁶ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
⁸⁷ Department of Epidemiology, Harvard T. H. School of Public Health, Boston, MA, USA.
⁸⁸ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
⁸⁹ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
⁹⁰ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.

^# Contributed equally.

PMID: 36131047
PMCID: PMC9763110
DOI: 10.1038/s41380-022-01776-4

Abstract

Posttraumatic stress disorder (PTSD) is a heritable (h² = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10^-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

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Conflict of interest statement

MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, RCK has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. MU has been a consultant for System Analytic. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Fig. 1. Genome-wide CNV burden association.**
The bar plot depicts regression beta coefficients as effect sizes (on the x-axis) of genome-wide CNV burden on PTSD, including overall burden, overlapping neurodevelopmental regions only, and genome-wide with neurodevelopmental regions excluded (on the y-axis). Data are shown stratified by CNV type, both CNV types (colored black), duplications only (colored red), and deletions only (colored blue). Effect sizes are shown in terms of megabases of the genome spanned by CNV.

**Fig. 2. Association of individual NDD CNVs with PTSD.**
The bar plot depicts regression beta coefficients as effect sizes (on the x-axis) of NDD CNVs (on the y-axis) on PTSD. Data are colored by CNV type, with deletions in blue and duplications in red. Effect sizes are shown in terms of megabases of the genome spanned by CNV. A star indicates an FDR significant CNVs.

See this image and copyright information in PMC

References

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Rare copy number variation in posttraumatic stress disorder

Affiliations

Rare copy number variation in posttraumatic stress disorder

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Abstract

Conflict of interest statement

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