Rare copy number variation in posttraumatic stress disorder

Adam X Maihofer; Worrawat Engchuan; Guillaume Huguet; Marieke Klein; Jeffrey R MacDonald; Omar Shanta; Bhooma Thiruvahindrapuram; Martineau Jean-Louis; Zohra Saci; Sebastien Jacquemont; Stephen W Scherer; Elizabeth Ketema; Allison E Aiello; Ananda B Amstadter; Esmina Avdibegović; Dragan Babic; Dewleen G Baker; Jonathan I Bisson; Marco P Boks; Elizabeth A Bolger; Richard A Bryant; Angela C Bustamante; Jose Miguel Caldas-de-Almeida; Graça Cardoso; Jurgen Deckert; Douglas L Delahanty; Katharina Domschke; Boadie W Dunlop; Alma Dzubur-Kulenovic; Alexandra Evans; Norah C Feeny; Carol E Franz; Aarti Gautam; Elbert Geuze; Aferdita Goci; Rasha Hammamieh; Miro Jakovljevic; Marti Jett; Ian Jones; Milissa L Kaufman; Ronald C Kessler; Anthony P King; William S Kremen; Bruce R Lawford; Lauren A M Lebois; Catrin Lewis; Israel Liberzon; Sarah D Linnstaedt; Bozo Lugonja; Jurjen J Luykx; Michael J Lyons; Matig R Mavissakalian; Katie A McLaughlin; Samuel A McLean; Divya Mehta; Rebecca Mellor; Charles Phillip Morris; Seid Muhie; Holly K Orcutt; Matthew Peverill; Andrew Ratanatharathorn; Victoria B Risbrough; Albert Rizzo; Andrea L Roberts; Alex O Rothbaum; Barbara O Rothbaum; Peter Roy-Byrne; Kenneth J Ruggiero; Bart P F Rutten; Dick Schijven; Julia S Seng; Christina M Sheerin; Michael A Sorenson; Martin H Teicher; Monica Uddin; Robert J Ursano; Christiaan H Vinkers; Joanne Voisey; Heike Weber; Sherry Winternitz; Miguel Xavier; Ruoting Yang; Ross McD Young; Lori A Zoellner; Rany M Salem; Richard A Shaffer; Tianying Wu; Kerry J Ressler; Murray B Stein; Karestan C Koenen; Jonathan Sebat; Caroline M Nievergelt

doi:10.1038/s41380-022-01776-4

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Rare copy number variation in posttraumatic stress disorder

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Rare copy number variation in posttraumatic stress disorder

Adam X Maihofer, Worrawat Engchuan, Guillaume Huguet, Marieke Klein, Jeffrey R MacDonald, Omar Shanta, Bhooma Thiruvahindrapuram, Martineau Jean-Louis, Zohra Saci, Sebastien Jacquemont, …

Molecular Psychiatry, Vol.27, pp.5062-5069

2022

DOI: https://doi.org/10.1038/s41380-022-01776-4

PMCID: PMC9763110

PMID: 36131047

Appears in UniSC Diversity and Inclusion Research Collection

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Abstract

UniSC Diversity Area - Disability and Inclusion

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.

Details

Title: Rare copy number variation in posttraumatic stress disorder
Authors: Adam X Maihofer (Corresponding Author) - University of California San Diego
Worrawat Engchuan (Author)
Guillaume Huguet (Author) - Centre Hospitalier Universitaire Sainte-Justine
Marieke Klein (Author) - University of California San Diego Medical Center
Jeffrey R MacDonald (Author)
Omar Shanta (Author) - University of California San Diego Medical Center
Bhooma Thiruvahindrapuram (Author)
Martineau Jean-Louis (Author) - Centre Hospitalier Universitaire Sainte-Justine
Zohra Saci (Author) - Centre Hospitalier Universitaire Sainte-Justine
Sebastien Jacquemont (Author) - Centre Hospitalier Universitaire Sainte-Justine
Stephen W Scherer (Author) - University of Toronto
Elizabeth Ketema (Author) - University of California San Diego Medical Center
Allison E Aiello (Author) - Columbia University
Ananda B Amstadter (Author) - Virginia Institute for Psychiatric and Behavioral Genetics
Esmina Avdibegović (Author) - University Clinical Center Tuzla
Dragan Babic (Author) - University Clinical Hospital Mostar
Dewleen G Baker (Author) - University of California San Diego
Jonathan I Bisson (Author) - Cardiff University
Marco P Boks (Author) - UMC Utrecht Brain Center Rudolf Magnus
Elizabeth A Bolger (Author) - Harvard Medical School
Richard A Bryant (Author) - UNSW Australia
Angela C Bustamante (Author) - University of Michigan Medical School
Jose Miguel Caldas-de-Almeida (Author) - Lisbon Institute of Global Mental Health
Graça Cardoso (Author) - Lisbon Institute of Global Mental Health
Jurgen Deckert (Author) - University Hospital of Würzburg
Douglas L Delahanty (Author) - Kent State University
Katharina Domschke (Author) - University of Freiburg
Boadie W Dunlop (Author) - Emory University School of Medicine
Alma Dzubur-Kulenovic (Author) - University of Sarajevo
Alexandra Evans (Author) - Cardiff University
Norah C Feeny (Author) - Case Western Reserve University
Carol E Franz (Author) - University of California San Diego
Aarti Gautam (Author) - Walter Reed Army Institute of Research
Elbert Geuze (Author) - UMC Utrecht Brain Center Rudolf Magnus
Aferdita Goci (Author) - University Clinical Center of Kosovo
Rasha Hammamieh (Author) - Walter Reed Army Institute of Research
Miro Jakovljevic (Author) - University of Zagreb
Marti Jett (Author) - Walter Reed Army Institute of Research
Ian Jones (Author) - Cardiff University
Milissa L Kaufman (Author) - Harvard Medical School
Ronald C Kessler (Author) - Harvard Medical School
Anthony P King (Author) - Ohio State University Hospital
William S Kremen (Author) - University of California San Diego
Bruce R Lawford (Author) - Queensland University of Technology
Lauren A M Lebois (Author) - Harvard Medical School
Catrin Lewis (Author) - Cardiff University
Israel Liberzon (Author) - University of Michigan
Sarah D Linnstaedt (Author) - University of North Carolina at Chapel Hill
Bozo Lugonja (Author) - Cardiff University
Jurjen J Luykx (Author) - UMC Utrecht Brain Center Rudolf Magnus
Michael J Lyons (Author) - Boston University
Matig R Mavissakalian (Author) - Cleveland University
Katie A McLaughlin (Author) - Harvard University
Samuel A McLean (Author) - UNC Institute for Trauma Recovery
Divya Mehta (Author) - Queensland University of Technology
Rebecca Mellor (Author) - Greenslopes Private Hospital
Charles Phillip Morris (Author) - Queensland University of Technology
Seid Muhie (Author) - Walter Reed Army Institute of Research
Holly K Orcutt (Author) - Northern Illinois University
Matthew Peverill (Author) - University of Washington
Andrew Ratanatharathorn (Author) - Columbia University
Victoria B Risbrough (Author) - University of California San Diego Medical Center
Albert Rizzo (Author) - University of Southern California
Andrea L Roberts (Author) - Harvard T.H. Chan School of Public Health
Alex O Rothbaum (Author) - Medical University of South Carolina
Barbara O Rothbaum (Author) - Emory University Hospital
Peter Roy-Byrne (Author) - University of Washington
Kenneth J Ruggiero (Author) - Medical University of South Carolina
Bart P F Rutten (Author) - Maastricht University
Dick Schijven (Author) - UMC Utrecht Brain Center Rudolf Magnus
Julia S Seng (Author) - University of Michigan Medical School
Christina M Sheerin (Author) - Virginia Institute for Psychiatric and Behavioral Genetics
Michael A Sorenson (Author) - University of California San Diego Medical Center
Martin H Teicher (Author) - Harvard Medical School
Monica Uddin (Author) - University of Florida
Robert J Ursano (Author) - Uniformed Services University of the Health Sciences
Christiaan H Vinkers (Author) - Vrije Universiteit Amsterdam
Joanne Voisey (Author) - Queensland University of Technology
Heike Weber (Author) - University of Würzburg
Sherry Winternitz (Author) - Harvard Medical School
Miguel Xavier (Author) - Universidade Nova de Lisboa
Ruoting Yang (Author) - Walter Reed Army Institute of Research
Ross McD Young (Author) - University of the Sunshine Coast, Queensland, Office of the Deputy Vice-Chancellor (Research and Innovation)
Lori A Zoellner (Author) - University of Washington
Rany M Salem (Author) - University of California San Diego Medical Center
Richard A Shaffer (Author)
Tianying Wu (Author) - San Diego State University
Kerry J Ressler (Author) - Harvard Medical School
Murray B Stein (Author) - University of California San Diego
Karestan C Koenen (Author) - Harvard T.H. Chan School of Public Health
Jonathan Sebat (Author) - University of California San Diego Medical Center
Caroline M Nievergelt (Author) - University of California San Diego
Publication details: Molecular Psychiatry, Vol.27, pp.5062-5069
Publisher: Nature Publishing Group
Date published: 2022
DOI: 10.1038/s41380-022-01776-4
ISSN: 1476-5578
PMID: 36131047; PMC9763110
Copyright note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/.
Organisation Unit: Office of the Deputy Vice-Chancellor (Research and Innovation); School of Health and Sport Sciences - Legacy
Language: English
Record Identifier: 99678898602621
Output Type: Journal article

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