Seyma Katrinli1, Adriana Lori2, Varun Kilaru1, Sierra Carter3, Abigail Powers2, Charles F Gillespie2, Aliza P Wingo4, Vasiliki Michopoulos2, Tanja Jovanovic2, Kerry J Ressler5, Alicia K Smith6. 1. Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA. 2. Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA. 3. Department of Psychology, Georgia State University, Atlanta, GA, USA. 4. Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA; Division of Mental Health, Atlanta VA Medical Center, Decatur, GA, USA. 5. Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA; Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA. 6. Emory University, Department of Gynecology and Obstetrics, Atlanta, GA, USA; Emory University, Department of Psychiatry & Behavioral Sciences, Atlanta, GA, USA. Electronic address: alicia.smith@emory.edu.
Abstract
BACKGROUND: Immune dysregulation has been widely observed in those with posttraumatic stress disorder (PTSD). An individual's immune response is shaped, in part, by the highly polymorphic Human Leukocyte Antigen (HLA) locus that is associated with major psychiatric disorders such as schizophrenia, major depression and bipolar disorder. The aim of the current study was to investigate the association between common HLA alleles and PTSD. METHODS: Genome-wide association data was used to predict alleles of 7 classical polymorphic HLA genes (A, B, C, DRB1, DQA1, DQB1, DPB1) in 403 lifetime PTSD cases and 369 trauma exposed controls of African ancestry. Association of HLA allelic variations with lifetime PTSD was analyzed using logistic regression, controlling for ancestry, sex and multiple comparisons. The effect of HLA alleles on gene expression was assessed by weighted correlation network analysis (WGCNA), using 353 subjects with available expression data. Enrichment analysis was performed using anRichment to identify associated pathways of each module. RESULTS: HLA-B*58:01 (p = 0.035), HLA-C*07:01 (p = 0.035), HLA-DQA1*01:01 (p = 0.003), HLA-DQB1*05:01 (p = 0.009) and HLA-DPB1*17:01 (p = 0.017) were more common in PTSD cases, while HLA-A*02:01 (p = 0.026), HLA-DQA1*05:05 (p = 0.011) and HLA-DRB1*11:01 (p < 0.001) were more frequent in controls. WGCNA was used to explore expression patterns of the PTSD related alleles. Gene expression modules of PTSD-related HLA alleles were enriched in various pathways, including pathways related to immune and neural activity. CONCLUSIONS: To the best of our knowledge, this is the first study to report an association of HLA alleles with PTSD. Altogether, our results support the link between the immune system, brain and PTSD.
BACKGROUND: Immune dysregulation has been widely observed in those with posttraumatic stress disorder (PTSD). An individual's immune response is shaped, in part, by the highly polymorphic Human Leukocyte Antigen (HLA) locus that is associated with major psychiatric disorders such as schizophrenia, major depression and bipolar disorder. The aim of the current study was to investigate the association between common HLA alleles and PTSD. METHODS: Genome-wide association data was used to predict alleles of 7 classical polymorphic HLA genes (A, B, C, DRB1, DQA1, DQB1, DPB1) in 403 lifetime PTSD cases and 369 trauma exposed controls of African ancestry. Association of HLA allelic variations with lifetime PTSD was analyzed using logistic regression, controlling for ancestry, sex and multiple comparisons. The effect of HLA alleles on gene expression was assessed by weighted correlation network analysis (WGCNA), using 353 subjects with available expression data. Enrichment analysis was performed using anRichment to identify associated pathways of each module. RESULTS:HLA-B*58:01 (p = 0.035), HLA-C*07:01 (p = 0.035), HLA-DQA1*01:01 (p = 0.003), HLA-DQB1*05:01 (p = 0.009) and HLA-DPB1*17:01 (p = 0.017) were more common in PTSD cases, while HLA-A*02:01 (p = 0.026), HLA-DQA1*05:05 (p = 0.011) and HLA-DRB1*11:01 (p < 0.001) were more frequent in controls. WGCNA was used to explore expression patterns of the PTSD related alleles. Gene expression modules of PTSD-related HLA alleles were enriched in various pathways, including pathways related to immune and neural activity. CONCLUSIONS: To the best of our knowledge, this is the first study to report an association of HLA alleles with PTSD. Altogether, our results support the link between the immune system, brain and PTSD.
Authors: Lynn M Almli; Adriana Lori; Jacquelyn L Meyers; Jaemin Shin; Negar Fani; Adam X Maihofer; Caroline M Nievergelt; Alicia K Smith; Kristina B Mercer; Kimberly Kerley; Jennifer M Leveille; Hao Feng; Duna Abu-Amara; Janine D Flory; Rachel Yehuda; Charles R Marmar; Dewleen G Baker; Bekh Bradley; Karestan C Koenen; Karen N Conneely; Kerry J Ressler Journal: Addict Biol Date: 2017-10-30 Impact factor: 4.280
Authors: Vasiliki Michopoulos; Alex O Rothbaum; Tanja Jovanovic; Lynn M Almli; Bekh Bradley; Barbara O Rothbaum; Charles F Gillespie; Kerry J Ressler Journal: Am J Psychiatry Date: 2014-12-12 Impact factor: 18.112
Authors: Ann C Schwartz; Rebekah Bradley; Kristin M Penza; Melissa Sexton; Daniel Jay; Patrick J Haggard; Steven J Garlow; Kerry J Ressler Journal: Psychosomatics Date: 2006 Mar-Apr Impact factor: 2.386
Authors: S E Bergen; C T O'Dushlaine; S Ripke; P H Lee; D M Ruderfer; S Akterin; J L Moran; K D Chambert; R E Handsaker; L Backlund; U Ösby; S McCarroll; M Landen; E M Scolnick; P K E Magnusson; P Lichtenstein; C M Hultman; S M Purcell; P Sklar; P F Sullivan Journal: Mol Psychiatry Date: 2012-06-12 Impact factor: 15.992
Authors: Charles F Gillespie; Bekh Bradley; Kristie Mercer; Alicia K Smith; Karen Conneely; Mark Gapen; Tamara Weiss; Ann C Schwartz; Joseph F Cubells; Kerry J Ressler Journal: Gen Hosp Psychiatry Date: 2009-06-09 Impact factor: 3.238
Authors: Divya Mehta; Torsten Klengel; Karen N Conneely; Alicia K Smith; André Altmann; Thaddeus W Pace; Monika Rex-Haffner; Anne Loeschner; Mariya Gonik; Kristina B Mercer; Bekh Bradley; Bertram Müller-Myhsok; Kerry J Ressler; Elisabeth B Binder Journal: Proc Natl Acad Sci U S A Date: 2013-04-29 Impact factor: 11.205
Authors: Samuel Parks; Dimitrios Avramopoulos; Jennifer Mulle; John McGrath; Ruihua Wang; Fernando S Goes; Karen Conneely; Ingo Ruczinski; Robert Yolken; Ann E Pulver; Brad D Pearce Journal: Brain Behav Immun Date: 2018-03-21 Impact factor: 7.217
Authors: Jeremy A Miller; Chaochao Cai; Peter Langfelder; Daniel H Geschwind; Sunil M Kurian; Daniel R Salomon; Steve Horvath Journal: BMC Bioinformatics Date: 2011-08-04 Impact factor: 3.169
Authors: O A Andreassen; H F Harbo; Y Wang; W K Thompson; A J Schork; M Mattingsdal; V Zuber; F Bettella; S Ripke; J R Kelsoe; K S Kendler; M C O'Donovan; P Sklar; L K McEvoy; R S Desikan; B A Lie; S Djurovic; A M Dale Journal: Mol Psychiatry Date: 2014-01-28 Impact factor: 15.992
Authors: Diana L Núñez-Rios; José J Martínez-Magaña; Sheila T Nagamatsu; Diego E Andrade-Brito; Diego A Forero; Carlos A Orozco-Castaño; Janitza L Montalvo-Ortiz Journal: Biomedicines Date: 2022-05-10
Authors: Clara Snijders; Adam X Maihofer; Andrew Ratanatharathorn; Dewleen G Baker; Marco P Boks; Elbert Geuze; Sonia Jain; Ronald C Kessler; Ehsan Pishva; Victoria B Risbrough; Murray B Stein; Robert J Ursano; Eric Vermetten; Christiaan H Vinkers; Alicia K Smith; Monica Uddin; Bart P F Rutten; Caroline M Nievergelt Journal: Clin Epigenetics Date: 2020-01-13 Impact factor: 6.551
Authors: Rafael Leite Dantas; Jana Freff; Oliver Ambrée; Eva C Beins; Andreas J Forstner; Udo Dannlowski; Bernhard T Baune; Stefanie Scheu; Judith Alferink Journal: Cells Date: 2021-04-19 Impact factor: 6.600
Authors: Seyma Katrinli; Nayara C S Oliveira; Jennifer C Felger; Vasiliki Michopoulos; Alicia K Smith Journal: Transl Psychiatry Date: 2022-08-04 Impact factor: 7.989
Authors: Seyma Katrinli; Yuanchao Zheng; Aarti Gautam; Rasha Hammamieh; Ruoting Yang; Suresh Venkateswaran; Varun Kilaru; Adriana Lori; Rebecca Hinrichs; Abigail Powers; Charles F Gillespie; Aliza P Wingo; Vasiliki Michopoulos; Tanja Jovanovic; Erika J Wolf; Regina E McGlinchey; William P Milberg; Mark W Miller; Subra Kugathasan; Marti Jett; Mark W Logue; Kerry J Ressler; Alicia K Smith Journal: Brain Behav Immun Date: 2020-11-03 Impact factor: 7.217