Rare copy number variation in posttraumatic stress disorder
Authors: Maihofer Adam X. , Engchuan Worrawat , Huguet Guillaume , Klein Marieke , MacDonald Jeffrey R. , Shanta Omar , Thiruvahindrapuram Bhooma , Jean-louis Martineau , Saci Zohra , Jacquemont Sebastien , Scherer Stephen W. , Ketema Elizabeth , Aiello Allison E. , Amstadter Ananda B. , Avdibegović Esmina , Babic Dragan , Baker Dewleen G. , Bisson Jonathan I. , Boks Marco P. , Bolger Elizabeth A. , Bryant Richard A. , Bustamante Angela C. , Caldas-de-Almeida Jose Miguel , Cardoso Graça , Deckert Jurgen , Delahanty Douglas L. , Domschke Katharina , Dunlop Boadie W. , Dzubur-Kulenovic Alma , Evans Alexandra , Feeny Norah C. , Franz Carol E. , Gautam Aarti , Geuze Elbert , Goci Aferdita , Hammamieh Rasha , Jakovljevic Miro , Jett Marti , Jones Ian , Kaufman Milissa L. , Kessler Ronald C. , King Anthony P. , Kremen William S. , Lawford Bruce R. , Lebois Lauren A. M. , Lewis Catrin , Liberzon Israel , Linnstaedt Sarah D. , Lugonja Bozo , Luykx Jurjen J. , Lyons Michael J. , Mavissakalian Matig R. , McLaughlin Katie A. , McLean Samuel A. , Mehta Divya , Mellor Rebecca , Morris Charles Phillip , Muhie Seid , Orcutt Holly K. , Peverill Matthew , Ratanatharathorn Andrew , Risbrough Victoria B. , Rizzo Albert , Roberts Andrea L. , Rothbaum Alex O. , Rothbaum Barbara O. , Roy-Byrne Peter , Ruggiero Kenneth J. , Rutten Bart P. F. , Schijven Dick , Seng Julia S. , Sheerin Christina M. , Sorenson Michael A. , Teicher Martin H. , Uddin Monica , Ursano Robert J. , Vinkers Christiaan H. , Voisey Joanne , Weber Heike , Winternitz Sherry , Xavier Miguel , Yang Ruoting , McD Young Ross , Zoellner Lori A. ,   Psychiatric Genomics Consortium PTSD Working Group,   Psychiatric Genomics Consortium CNV Working Group, Salem Rany M. , Shaffer Richard A. , Wu Tianying , Ressler Kerry J. , Stein Murray B. , Koenen Karestan C. , Sebat Jonathan , Nievergelt Caroline M. 
Published: September 2022

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 (FDRq < 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.