1. Rare copy number variation in posttraumatic stress disorder
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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, MUMC+: MA Psychiatrie (3), Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Centro de Estudos de Doenças Crónicas (CEDOC), and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
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Stress Disorders, Post-Traumatic ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Genome ,SDG 3 - Good Health and Well-being ,DNA Copy Number Variations ,Humans ,Brain ,Genetic Predisposition to Disease ,Molecular Biology ,Polymorphism, Single Nucleotide ,Genome-Wide Association Study - Abstract
Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). 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. publishersversion published
- Published
- 2022
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