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2. Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts

Author

Wani, Agaz H., Katrinli, Seyma, Zhao, Xiang, Daskalakis, Nikolaos P., Zannas, Anthony S., Aiello, Allison E., Baker, Dewleen G., Boks, Marco P., Brick, Leslie A., Chen, Chia-Yen, Dalvie, Shareefa, Fortier, Catherine, Geuze, Elbert, Hayes, Jasmeet P., Kessler, Ronald C., King, Anthony P., Koen, Nastassja, Liberzon, Israel, Lori, Adriana, Luykx, Jurjen J., Maihofer, Adam X., Milberg, William, Miller, Mark W., Mufford, Mary S., Nugent, Nicole R., Rauch, Sheila, Ressler, Kerry J., Risbrough, Victoria B., Rutten, Bart P. F., Stein, Dan J., Stein, Murray B., Ursano, Robert J., Verfaellie, Mieke H., Vermetten, Eric, Vinkers, Christiaan H., Ware, Erin B., Wildman, Derek E., Wolf, Erika J., Nievergelt, Caroline M., Logue, Mark W., Smith, Alicia K., and Uddin, Monica

Published
2024
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3. Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Author

Nievergelt, Caroline M., Maihofer, Adam X., Atkinson, Elizabeth G., Chen, Chia-Yen, Choi, Karmel W., Coleman, Jonathan R. I., Daskalakis, Nikolaos P., Duncan, Laramie E., Polimanti, Renato, Aaronson, Cindy, Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegoviç, Esmina, Babić, Dragan, Bacanu, Silviu-Alin, Baker, Dewleen G., Batzler, Anthony, Beckham, Jean C., Belangero, Sintia, Benjet, Corina, Bergner, Carisa, Bierer, Linda M., Biernacka, Joanna M., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Brandolino, Amber, Breen, Gerome, Bressan, Rodrigo Affonseca, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Børglum, Anders D., Børte, Sigrid, Cahn, Leah, Calabrese, Joseph R., Caldas-de-Almeida, Jose Miguel, Chatzinakos, Chris, Cheema, Sheraz, Clouston, Sean A. P., Colodro-Conde, Lucía, Coombes, Brandon J., Cruz-Fuentes, Carlos S., Dale, Anders M., Dalvie, Shareefa, Davis, Lea K., Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Desarnaud, Frank, DiPietro, Christopher P., Disner, Seth G., Docherty, Anna R., Domschke, Katharina, Dyb, Grete, Kulenović, Alma Džubur, Edenberg, Howard J., Evans, Alexandra, Fabbri, Chiara, Fani, Negar, Farrer, Lindsay A., Feder, Adriana, Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Goleva, Slavina B., Gordon, Scott D., Goçi, Aferdita, Grasser, Lana Ruvolo, Guindalini, Camila, Haas, Magali, Hagenaars, Saskia, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M. J., Hesselbrock, Victor, Hickie, Ian B., Hogan, Kelleigh, Hougaard, David Michael, Huang, Hailiang, Huckins, Laura M., Hveem, Kristian, Jakovljević, Miro, Javanbakht, Arash, Jenkins, Gregory D., Johnson, Jessica, Jones, Ian, Jovanovic, Tanja, Karstoft, Karen-Inge, Kaufman, Milissa L., Kennedy, James L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kotov, Roman, Kranzler, Henry R., Krebs, Kristi, Kremen, William S., Kuan, Pei-Fen, Lawford, Bruce R., Lebois, Lauren A. M., Lehto, Kelli, Levey, Daniel F., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lu, Yi, Luft, Benjamin J., Lupton, Michelle K., Luykx, Jurjen J., Makotkine, Iouri, Maples-Keller, Jessica L., Marchese, Shelby, Marmar, Charles, Martin, Nicholas G., Martínez-Levy, Gabriela A., McAloney, Kerrie, McFarlane, Alexander, McLaughlin, Katie A., McLean, Samuel A., Medland, Sarah E., Mehta, Divya, Meyers, Jacquelyn, Michopoulos, Vasiliki, Mikita, Elizabeth A., Milani, Lili, Milberg, William, Miller, Mark W., Morey, Rajendra A., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben Bo, Mufford, Mary S., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., Nugent, Nicole R., O’Donnell, Meaghan, Orcutt, Holly K., Pan, Pedro M., Panizzon, Matthew S., Pathak, Gita A., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Porjesz, Bernice, Powers, Abigail, Qin, Xue-Jun, Ratanatharathorn, Andrew, Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Runz, Heiko, Rutten, Bart P. F., de Viteri, Stacey Saenz, Salum, Giovanni Abrahão, Sampson, Laura, Sanchez, Sixto E., Santoro, Marcos, Seah, Carina, Seedat, Soraya, Seng, Julia S., Shabalin, Andrey, Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stensland, Synne, Stevens, Jennifer S., Sumner, Jennifer A., Teicher, Martin H., Thompson, Wesley K., Tiwari, Arun K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., Valdimarsdóttir, Unnur, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Waszczuk, Monika, Weber, Heike, Wendt, Frank R., Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winsvold, Bendik S., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Xia, Yan, Xiong, Ying, Yehuda, Rachel, Young, Keith A., Young, Ross McD, Zai, Clement C., Zai, Gwyneth C., Zervas, Mark, Zhao, Hongyu, Zoellner, Lori A., Zwart, John-Anker, deRoon-Cassini, Terri, van Rooij, Sanne J. H., van den Heuvel, Leigh L., Stein, Murray B., Ressler, Kerry J., and Koenen, Karestan C.

Published
2024
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4. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Author

Meng, Xiangrui, Navoly, Georgina, Giannakopoulou, Olga, Levey, Daniel F., Koller, Dora, Pathak, Gita A., Koen, Nastassja, Lin, Kuang, Adams, Mark J., Rentería, Miguel E., Feng, Yanzhe, Gaziano, J. Michael, Stein, Dan J., Zar, Heather J., Campbell, Megan L., van Heel, David A., Trivedi, Bhavi, Finer, Sarah, McQuillin, Andrew, Bass, Nick, Chundru, V. Kartik, Martin, Hilary C., Huang, Qin Qin, Valkovskaya, Maria, Chu, Chia-Yi, Kanjira, Susan, Kuo, Po-Hsiu, Chen, Hsi-Chung, Tsai, Shih-Jen, Liu, Yu-Li, Kendler, Kenneth S., Peterson, Roseann E., Cai, Na, Fang, Yu, Sen, Srijan, Scott, Laura J., Burmeister, Margit, Loos, Ruth J. F., Preuss, Michael H., Actkins, Ky’Era V., Davis, Lea K., Uddin, Monica, Wani, Agaz H., Wildman, Derek E., Aiello, Allison E., Ursano, Robert J., Kessler, Ronald C., Kanai, Masahiro, Okada, Yukinori, Sakaue, Saori, Rabinowitz, Jill A., Maher, Brion S., Uhl, George, Eaton, William, Cruz-Fuentes, Carlos S., Martinez-Levy, Gabriela A., Campos, Adrian I., Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wassertheil-Smoller, Sylvia, Jiang, Yunxuan, Tian, Chao, Martin, Nicholas G., Mitchell, Brittany L., Byrne, Enda M., Awasthi, Swapnil, Coleman, Jonathan R. I., Ripke, Stephan, Sofer, Tamar, Walters, Robin G., McIntosh, Andrew M., Polimanti, Renato, Dunn, Erin C., Stein, Murray B., Gelernter, Joel, Lewis, Cathryn M., and Kuchenbaecker, Karoline

Published
2024
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5. Rare copy number variation in posttraumatic stress disorder

Author

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 AM, 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 PF, 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, Salem, Rany M, Shaffer, Richard A, Wu, Tianying, Ressler, Kerry J, Stein, Murray B, Koenen, Karestan C, Sebat, Jonathan, and Nievergelt, Caroline M

Subjects
Post-Traumatic Stress Disorder (PTSD), Mental Health, Human Genome, Genetics, Neurosciences, Brain Disorders, Mental health, Humans, DNA Copy Number Variations, Stress Disorders, Post-Traumatic, Genome, Brain, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Psychiatric Genomics Consortium PTSD Working Group, Psychiatric Genomics Consortium CNV Working Group, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
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

Published
2022

6. Epigenetics of early-life adversity in youth: cross-sectional and longitudinal associations

Author

Sumner, Jennifer A, Gambazza, Simone, Gao, Xu, Baccarelli, Andrea A, Uddin, Monica, and McLaughlin, Katie A

Subjects
Biological Sciences, Genetics, Pediatric, Violence Research, Mental Health, Human Genome, Clinical Research, Behavioral and Social Science, Pediatric Research Initiative, 2.3 Psychological, social and economic factors, Aetiology, Good Health and Well Being, Adolescent, Adverse Childhood Experiences, Child, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Threat, Deprivation, Abuse, Neglect, DNA methylation, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundAltered DNA methylation (DNAm) may be one pathway through which early-life adversity (ELA) contributes to adverse mental and physical health outcomes. This study investigated whether the presence versus absence of ELA experiences reflecting the dimensions of threat and deprivation were associated with epigenome-wide DNAm cross-sectionally and longitudinally in a community-based sample of children and adolescents.MethodsIn 113 youths aged 8-16 years with wide variability in ELA, we examined associations of abuse (physical, sexual, emotional; indicating threat-related experiences) and neglect (emotional, physical; indicating deprivation-related experiences) with DNAm assessed with the Illumina EPIC BeadChip array, with DNA derived from saliva. In cross-sectional epigenome-wide analyses, we investigated associations of lifetime abuse and neglect with DNAm at baseline. In longitudinal epigenome-wide analyses, we examined whether experiencing abuse and neglect over an approximately 2-year follow-up were each associated with change in DNAm from baseline to follow-up.ResultsIn cross-sectional analyses adjusting for lifetime experience of neglect, lifetime experience of abuse was associated with DNAm for four cytosine-phosphodiester-guanine (CpG) sites (cg20241299: coefficient = 0.023, SE = 0.004; cg08671764: coefficient = 0.018, SE = 0.003; cg27152686: coefficient = - 0.069, SE = 0.012; cg24241897: coefficient = - 0.003, SE = 0.001; FDR

Published
2022

8. A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke

Author

Soremekun, Opeyemi, Musanabaganwa, Clarisse, Uwineza, Annette, Ardissino, Maddalena, Rajasundaram, Skanda, Wani, Agaz H., Jansen, Stefan, Mutabaruka, Jean, Rutembesa, Eugene, Soremekun, Chisom, Cheickna, Cisse, Wele, Mamadou, Mugisha, Joseph, Nash, Oyekanmi, Kinyanda, Eugene, Nitsch, Dorothea, Fornage, Myriam, Chikowore, Tinashe, Gill, Dipender, Wildman, Derek E., Mutesa, Leon, Uddin, Monica, and Fatumo, Segun

Published
2023
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9. Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress

Author

Katrinli, Seyma, Maihofer, Adam X, Wani, Agaz H, Pfeiffer, John R, Ketema, Elizabeth, Ratanatharathorn, Andrew, Baker, Dewleen G, Boks, Marco P, Geuze, Elbert, Kessler, Ronald C, Risbrough, Victoria B, Rutten, Bart PF, Stein, Murray B, Ursano, Robert J, Vermetten, Eric, Logue, Mark W, Nievergelt, Caroline M, Smith, Alicia K, and Uddin, Monica

Subjects
Human Genome, Mental Health, Post-Traumatic Stress Disorder (PTSD), Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Adaptor Proteins, Signal Transducing, DNA Methylation, Epigenesis, Genetic, Epigenome, Humans, Immune System, Male, Military Personnel, Oxidative Stress, Stress Disorders, Post-Traumatic, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.

Published
2022

12. Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder

Author

Snijders, Clara, Maihofer, Adam X, Ratanatharathorn, Andrew, Baker, Dewleen G, Boks, Marco P, Geuze, Elbert, Jain, Sonia, Kessler, Ronald C, Pishva, Ehsan, Risbrough, Victoria B, Stein, Murray B, Ursano, Robert J, Vermetten, Eric, Vinkers, Christiaan H, Smith, Alicia K, Uddin, Monica, Rutten, Bart PF, and Nievergelt, Caroline M

Subjects
Mental Health, Post-Traumatic Stress Disorder (PTSD), Anxiety Disorders, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adult, Case-Control Studies, Cell Cycle Proteins, Cohort Studies, CpG Islands, DNA Methylation, Epigenesis, Genetic, Epigenome, Genomics, Humans, Longitudinal Studies, Male, Military Personnel, Polymorphism, Single Nucleotide, Stress Disorders, Post-Traumatic, EWAS, Longitudinal, DNA methylation, Meta-analysis, Trauma, PTSD, Epigenetics, PGC PTSD EWAS Consortium, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.ResultsStage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.ConclusionsThis study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

Published
2020

13. Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Author

Smith, Alicia K, Ratanatharathorn, Andrew, Maihofer, Adam X, Naviaux, Robert K, Aiello, Allison E, Amstadter, Ananda B, Ashley-Koch, Allison E, Baker, Dewleen G, Beckham, Jean C, Boks, Marco P, Bromet, Evelyn, Dennis, Michelle, Galea, Sandro, Garrett, Melanie E, Geuze, Elbert, Guffanti, Guia, Hauser, Michael A, Katrinli, Seyma, Kilaru, Varun, Kessler, Ronald C, Kimbrel, Nathan A, Koenen, Karestan C, Kuan, Pei-Fen, Li, Kefeng, Logue, Mark W, Lori, Adriana, Luft, Benjamin J, Miller, Mark W, Naviaux, Jane C, Nugent, Nicole R, Qin, Xuejun, Ressler, Kerry J, Risbrough, Victoria B, Rutten, Bart PF, Stein, Murray B, Ursano, Robert J, Vermetten, Eric, Vinkers, Christiaan H, Wang, Lin, Youssef, Nagy A, INTRuST Clinical Consortium, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup, Uddin, Monica, and Nievergelt, Caroline M

Subjects
INTRuST Clinical Consortium, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup, Humans, Wounds and Injuries, Kynurenine, Repressor Proteins, Case-Control Studies, Cohort Studies, Stress Disorders, Post-Traumatic, DNA Methylation, Epigenesis, Genetic, Military Personnel, Female, Male, Basic Helix-Loop-Helix Transcription Factors, Epigenome, Stress Disorders, Post-Traumatic, Epigenesis, Genetic
Abstract

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Published
2020

15. The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study

Author

Maihofer, Adam X., Choi, Karmel W., Coleman, Jonathan R.I., Daskalakis, Nikolaos P., Denckla, Christy A., Ketema, Elizabeth, Morey, Rajendra A., Polimanti, Renato, Ratanatharathorn, Andrew, Torres, Katy, Wingo, Aliza P., Zai, Clement C., Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegovic, Esmina, Borglum, Anders D., Babic, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Bradley, Bekh, Brashear, Meghan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas-de-Almeida, Jose Miguel, Chen, Chia-Yen, Dale, Anders M., Dalvie, Shareefa, Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Duncan, Laramie E., Kulenovic, Alma Dzubur, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gautam, Aarti, Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Uka, Aferdita Goci, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M.J., Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Karstoft, Karen-Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A.M., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica L., Marmar, Charles, Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., Mehta, Divya, Mellor, Rebecca, Michopoulos, Vasiliki, Milberg, William, Miller, Mark W., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben Bo, Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Rutten, Bart P.F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stevens, Jennifer S., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., Luella van den Heuvel, Leigh, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan, Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Yehuda, Rachel, Young, Keith A., Young, Ross McD., Zhao, Hongyu, Zoellner, Lori A., Haas, Magali, Lasseter, Heather, Provost, Allison C., Salem, Rany M., Sebat, Jonathan, Shaffer, Richard, Wu, Tianying, Ripke, Stephan, Daly, Mark J., Ressler, Kerry J., Koenen, Karestan C., Stein, Murray B., Nievergelt, Caroline M., Wendt, Frank R., Garcia-Argibay, Miguel, Cabrera-Mendoza, Brenda, Valdimarsdóttir, Unnur A., Nivard, Michel G., Larsson, Henrik, Mattheisen, Manuel, and Meier, Sandra M.

Published
2023
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17. Stressful life events and accelerated biological aging over time in youths

Author

Sumner, Jennifer A, Gao, Xu, Gambazza, Simone, Dye, Christian K, Colich, Natalie L, Baccarelli, Andrea A, Uddin, Monica, and McLaughlin, Katie A

Subjects
Behavioral and Social Science, Depression, Pediatric, Aging, Clinical Research, Genetics, Mental Health, Good Health and Well Being, Adolescent, Humans, Cross-Sectional Studies, DNA Methylation, Life Change Events, Stress, Psychological, Adolescents, Adversity, DNA methylation age, Epigenetic age, Pubertal stage, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Experiencing adversity in childhood and adolescence, including stressful life events (SLEs), may accelerate the pace of development, leading to adverse mental and physical health. However, most research on adverse early experiences and biological aging (BA) in youths relies on cross-sectional designs. In 171 youths followed for approximately 2 years, we examined if SLEs over follow-up predicted rate of change in two BA metrics: epigenetic age and Tanner stage. We also investigated if rate of change in BA was associated with changes in depressive symptoms over time. Youths aged 8-16 years at baseline self-reported Tanner stage and depressive symptoms at baseline and follow-up and provided saliva samples for DNA at both assessments. Horvath epigenetic age estimates were derived from DNA methylation data measured with the Illumina EPIC array. At follow-up, contextual threat interviews were administered to youths and caregivers to assess youths' experiences of past-year SLEs. Interviews were objectively coded by an independent rating team to generate a SLE impact score, reflecting the severity of all SLEs occurring over the prior year. Rate of change in BA metrics was operationalized as change in epigenetic age or Tanner stage as a function of time between assessments. Higher objective SLE impact scores over follow-up were related to a greater rate of change in epigenetic age (β = 0.21, p = .043). Additionally, among youths with lower-but not higher-Tanner stage at baseline, there was a positive association of SLE impact scores with rate of change in Tanner stage (Baseline Tanner Stage × SLE Impact Score interaction: β = - 0.21, p = .011). A greater rate of change in epigenetic age was also associated with higher depressive symptom levels at follow-up, adjusting for baseline symptoms (β = 0.15, p = .043). Associations with epigenetic age were similar, although slightly attenuated, when adjusting for epithelial (buccal) cell proportions. Whereas much research in youths has focused on severe experiences of early adversity, we demonstrate that more commonly experienced SLEs during adolescence may also contribute to accelerated BA. Further research is needed to understand the long-term consequences of changes in BA metrics for health.

Published
2023

20. Genomic Approaches to Posttraumatic Stress Disorder: The Psychiatric Genomic Consortium Initiative

Author

Nievergelt, Caroline M, Ashley-Koch, Allison E, Dalvie, Shareefa, Hauser, Michael A, Morey, Rajendra A, Smith, Alicia K, and Uddin, Monica

Subjects
Biological Psychology, Biological Sciences, Genetics, Psychology, Mental Health, Human Genome, Anxiety Disorders, Biotechnology, Clinical Research, Prevention, Post-Traumatic Stress Disorder (PTSD), Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Epigenomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Stress Disorders, Post-Traumatic, Epigenetics, Gene expression, Imaging, Psychiatric Genomics Consortium, Systems biology, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences
Abstract

Posttraumatic stress disorder (PTSD) after exposure to a traumatic event is a highly prevalent psychiatric disorder. Heritability estimates from twin studies as well as from recent molecular data (single nucleotide polymorphism-based heritability) indicate moderate to high heritability, yet robust genetic variants for PTSD have not yet been identified and the genetic architecture of this polygenic disorder remains largely unknown. To date, fewer than 10 large-scale genome-wide association studies of PTSD have been published, with findings that highlight the unique challenges for PTSD genomics, including a complex diagnostic entity with contingency of PTSD diagnosis on trauma exposure and the large genetic diversity of the study populations. The Psychiatric Genomics Consortium PTSD group has brought together more than 200 scientists with the goal to increase sample size for genome-wide association studies and other genomic analyses to sufficient numbers where robust discoveries of molecular signatures can be achieved. The sample currently includes more than 32,000 PTSD cases and 100,000 trauma-exposed control subjects, and collection is ongoing. The first results found a significant shared genetic risk of PTSD with other psychiatric disorders and sex-biased heritability estimates with higher heritability in female individuals compared with male individuals. This review describes the scope and current focus of the Psychiatric Genomics Consortium PTSD group and its expansion from the initial genome-wide association study group to nine working groups, including epigenetics, gene expression, imaging, and integrative systems biology. We further briefly outline recent findings and future directions of "omics"-based studies of PTSD, with the ultimate goal of elucidating the molecular architecture of this complex disorder to improve prevention and intervention strategies.

Published
2018

22. Epigenome-Wide Meta-Analysis of 11 Military and Civilian Cohorts Reveals Cell-Type Specific and Inflammatory DNA Methylation Patterns Associated With PTSD

Author

Katrinli, Seyma, primary, Wani, Agaz, additional, Zhao, Xiang, additional, Maihofer, Adam X., additional, Zhao, Ying, additional, Nunez, Diana, additional, Montalvo-Ortiz, Janitza, additional, Zannas, Anthony, additional, Logue, Mark W., additional, Nievergelt, Caroline M., additional, Uddin, Monica, additional, and Smith, Alicia, additional

Published
2024
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25. Epigenome‐wide association of PTSD from heterogeneous cohorts with a common multi‐site analysis pipeline

Author

Ratanatharathorn, Andrew, Boks, Marco P, Maihofer, Adam X, Aiello, Allison E, Amstadter, Ananda B, Ashley‐Koch, Allison E, Baker, Dewleen G, Beckham, Jean C, Bromet, Evelyn, Dennis, Michelle, Garrett, Melanie E, Geuze, Elbert, Guffanti, Guia, Hauser, Michael A, Kilaru, Varun, Kimbrel, Nathan A, Koenen, Karestan C, Kuan, Pei‐Fen, Logue, Mark W, Luft, Benjamin J, Miller, Mark W, Mitchell, Colter, Nugent, Nicole R, Ressler, Kerry J, Rutten, Bart PF, Stein, Murray B, Vermetten, Eric, Vinkers, Christiaan H, Youssef, Nagy A, Workgroup, VA Mid‐Atlantic MIRECC, Workgroup, PGC PTSD Epigenetics, Uddin, Monica, Nievergelt, Caroline M, and Smith, Alicia K

Subjects
Human Genome, Genetics, Post-Traumatic Stress Disorder (PTSD), Mental Health, Anxiety Disorders, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Adult, Cohort Studies, DNA Methylation, Epigenomics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Male, Middle Aged, Phenotype, Stress Disorders, Post-Traumatic, EWAS, meta-analysis, stress, trauma, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup, Clinical Sciences, Neurosciences
Abstract

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.

Published
2017

26. Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts

Author

Onderzoeksgroep 2, Brain, Hersenen-Medisch 1, Wani, Agaz, Katrinli, Seyma, Zhao, Xiang, Daskalakis, Nikolaos, Zannas, Anthony, Aiello, Allison, Baker, Dewleen, Boks, Marco, Brick, Leslie, Chen, Chia-Yen, Dalvie, Shareefa, Fortier, Catherine, Geuze, Elbert, Hayes, Jasmeet, Kessler, Ronald, King, Anthony, Koen, Nastassja, Liberzon, Israel, Lori, Adriana, Luykx, Jurjen, Maihofer, Adam, Milberg, William, Miller, Mark, Mufford, Mary, Nugent, Nicole, Rauch, Sheila, Ressler, Kerry, Risbrough, Victoria, Rutten, Bart, Stein, Dan, Stein, Murrary, Ursano, Robert, Verfaellie, Mieke, Ware, Erin, Wildman, Derek, Wolf, Erika, Nievergelt, Caroline, Logue, Mark, Smith, Alicia, Uddin, Monica, Vermetten, Eric, Vinkers, Christiaan, Onderzoeksgroep 2, Brain, Hersenen-Medisch 1, Wani, Agaz, Katrinli, Seyma, Zhao, Xiang, Daskalakis, Nikolaos, Zannas, Anthony, Aiello, Allison, Baker, Dewleen, Boks, Marco, Brick, Leslie, Chen, Chia-Yen, Dalvie, Shareefa, Fortier, Catherine, Geuze, Elbert, Hayes, Jasmeet, Kessler, Ronald, King, Anthony, Koen, Nastassja, Liberzon, Israel, Lori, Adriana, Luykx, Jurjen, Maihofer, Adam, Milberg, William, Miller, Mark, Mufford, Mary, Nugent, Nicole, Rauch, Sheila, Ressler, Kerry, Risbrough, Victoria, Rutten, Bart, Stein, Dan, Stein, Murrary, Ursano, Robert, Verfaellie, Mieke, Ware, Erin, Wildman, Derek, Wolf, Erika, Nievergelt, Caroline, Logue, Mark, Smith, Alicia, Uddin, Monica, Vermetten, Eric, and Vinkers, Christiaan

Published
2024

27. Potential causal association between gut microbiome and posttraumatic stress disorder

Author

Cardiologie, Onderzoeksgroep 2, Brain, MGGZ, Hersenen-Medisch 1, Neurogenetica, Diagnostiek & Vroege Psychose Medisch, He, Qiang, Wang, Wenjing, Xu, Dingkang, Xiong, Yang, Tao, Chuanyuan, You, Chao, Ma, Lu, Ma, Junpeng, Nievergelt, Caroline M., Maihofer, Adam X., Klengel, Torsten, Atkinson, Elizabeth G., Chen, Chia Yen, Choi, Karmel W., Coleman, Jonathan R.I., Dalvie, Shareefa, Duncan, Laramie E., Logue, Mark W., Provost, Allison C., Ratanatharathorn, Andrew, Stein, Murray B., Torres, Katy, Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Søren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegovic, Esmina, Babić, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Børglum, Anders D., Bradley, Bekh, Brashear, Megan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas-de-Almeida, José M., Dale, Anders M., Daly, Mark J., Daskalakis, Nikolaos P., Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Dzubur-Kulenovic, Alma, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles, Uka, Aferdita Goci, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Harnal, Supriya, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M.J., Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue Jun, Junglen, Angela G., Karstoft, Karen Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A.M., Lewis, Catrin E., Linnstaedt, Sarah D., Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica, Marmar, Charles, Martin, Alicia R., Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., McLeay, Sarah, Mehta, Divya, Milberg, William P., Miller, Mark W., Morey, Rajendra A., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben B., Neale, Benjamin M., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Ripke, Stephan, Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Ken, Rung, Ariane, Rutten, Bart P.F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Solovieff, Nadia, Sponheim, Scott R., Stein, Dan J., Sumner, Jennifer A., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., van den Heuvel, Leigh Luella, van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Wolff, Jonathan D., Yehuda, Rachel, Young, Keith A., Young, Ross Mc D., Zhao, Hongyu, Zoellner, Lori A., Liberzon, Israel, Ressler, Kerry J., Haas, Magali, Koenen, Karestan C., Cardiologie, Onderzoeksgroep 2, Brain, MGGZ, Hersenen-Medisch 1, Neurogenetica, Diagnostiek & Vroege Psychose Medisch, He, Qiang, Wang, Wenjing, Xu, Dingkang, Xiong, Yang, Tao, Chuanyuan, You, Chao, Ma, Lu, Ma, Junpeng, Nievergelt, Caroline M., Maihofer, Adam X., Klengel, Torsten, Atkinson, Elizabeth G., Chen, Chia Yen, Choi, Karmel W., Coleman, Jonathan R.I., Dalvie, Shareefa, Duncan, Laramie E., Logue, Mark W., Provost, Allison C., Ratanatharathorn, Andrew, Stein, Murray B., Torres, Katy, Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Søren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegovic, Esmina, Babić, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Børglum, Anders D., Bradley, Bekh, Brashear, Megan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas-de-Almeida, José M., Dale, Anders M., Daly, Mark J., Daskalakis, Nikolaos P., Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Dzubur-Kulenovic, Alma, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles, Uka, Aferdita Goci, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Harnal, Supriya, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M.J., Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue Jun, Junglen, Angela G., Karstoft, Karen Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A.M., Lewis, Catrin E., Linnstaedt, Sarah D., Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica, Marmar, Charles, Martin, Alicia R., Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., McLeay, Sarah, Mehta, Divya, Milberg, William P., Miller, Mark W., Morey, Rajendra A., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben B., Neale, Benjamin M., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Ripke, Stephan, Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Ken, Rung, Ariane, Rutten, Bart P.F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Solovieff, Nadia, Sponheim, Scott R., Stein, Dan J., Sumner, Jennifer A., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., van den Heuvel, Leigh Luella, van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Wolff, Jonathan D., Yehuda, Rachel, Young, Keith A., Young, Ross Mc D., Zhao, Hongyu, Zoellner, Lori A., Liberzon, Israel, Ressler, Kerry J., Haas, Magali, and Koenen, Karestan C.

Published
2024

29. Differentially expressed heterogeneous overdispersion genes testing for count data.

Author

Yuan, Yubai, Xu, Qi, Wani, Agaz, Dahrendorff, Jan, Wang, Chengqi, Shen, Arlina, Donglasan, Janelle, Burgan, Sarah, Graham, Zachary, Uddin, Monica, Wildman, Derek, and Qu, Annie

Subjects
BIOLOGICAL systems, GENES, POISSON regression, STATISTICS, TEST methods, RNA sequencing
Abstract

The mRNA-seq data analysis is a powerful technology for inferring information from biological systems of interest. Specifically, the sequenced RNA fragments are aligned with genomic reference sequences, and we count the number of sequence fragments corresponding to each gene for each condition. A gene is identified as differentially expressed (DE) if the difference in its count numbers between conditions is statistically significant. Several statistical analysis methods have been developed to detect DE genes based on RNA-seq data. However, the existing methods could suffer decreasing power to identify DE genes arising from overdispersion and limited sample size, where overdispersion refers to the empirical phenomenon that the variance of read counts is larger than the mean of read counts. We propose a new differential expression analysis procedure: heterogeneous overdispersion genes testing (DEHOGT) based on heterogeneous overdispersion modeling and a post-hoc inference procedure. DEHOGT integrates sample information from all conditions and provides a more flexible and adaptive overdispersion modeling for the RNA-seq read count. DEHOGT adopts a gene-wise estimation scheme to enhance the detection power of differentially expressed genes when the number of replicates is limited as long as the number of conditions is large. DEHOGT is tested on the synthetic RNA-seq read count data and outperforms two popular existing methods, DESeq2 and EdgeR, in detecting DE genes. We apply the proposed method to a test dataset using RNAseq data from microglial cells. DEHOGT tends to detect more differently expressed genes potentially related to microglial cells under different stress hormones treatments. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts

Author

Wani, Agaz, primary, Katrinli, Seyma, additional, Zhao, Xiang, additional, Daskalakis, Nikolaos, additional, Zannas, Anthony, additional, Aiello, Allison, additional, Baker, Dewleen, additional, Boks, Marco, additional, Brick, Leslie, additional, Chen, Chia-Yen, additional, Dalvie, Shareefa, additional, Fortier, Catherine, additional, Geuze, Elbert, additional, Hayes, Jasmeet, additional, Kessler, Ronald, additional, King, Anthony, additional, Koen, Nastassja, additional, Liberzon, Israel, additional, Lori, Adriana, additional, Luykx, Jurjen, additional, Maihofer, Adam, additional, Milberg, William, additional, Miller, Mark, additional, Mufford, Mary, additional, Nugent, Nicole, additional, Rauch, Sheila, additional, Ressler, Kerry, additional, Risbrough, Victoria, additional, Rutten, Bart, additional, Stein, Dan, additional, Stein, Murrary, additional, Ursano, Robert, additional, Verfaellie, Mieke, additional, Ware, Erin, additional, Wildman, Derek, additional, Wolf, Erika, additional, Nievergelt, Caroline, additional, Logue, Mark, additional, Smith, Alicia, additional, Uddin, Monica, additional, Vermetten, Eric, additional, and Vinkers, Christiaan, additional

Published
2024
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35. Evaluating the impact of trauma and PTSD on epigenetic prediction of lifespan and neural integrity

Author

Katrinli, Seyma, Stevens, Jennifer, Wani, Agaz H., Lori, Adriana, Kilaru, Varun, van Rooij, Sanne J. H., Hinrichs, Rebecca, Powers, Abigail, Gillespie, Charles F., Michopoulos, Vasiliki, Gautam, Aarti, Jett, Marti, Hammamieh, Rasha, Yang, Ruoting, Wildman, Derek, Qu, Annie, Koenen, Karestan, Aiello, Allison E., Jovanovic, Tanja, Uddin, Monica, Ressler, Kerry J., and Smith, Alicia K.

Published
2020
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36. The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration

Author

Logue, Mark W, Amstadter, Ananda B, Baker, Dewleen G, Duncan, Laramie, Koenen, Karestan C, Liberzon, Israel, Miller, Mark W, Morey, Rajendra A, Nievergelt, Caroline M, Ressler, Kerry J, Smith, Alicia K, Smoller, Jordan W, Stein, Murray B, Sumner, Jennifer A, and Uddin, Monica

Subjects
Human Genome, Post-Traumatic Stress Disorder (PTSD), Brain Disorders, Anxiety Disorders, Serious Mental Illness, Schizophrenia, Genetics, Biotechnology, Mental Health, Clinical Research, Behavioral and Social Science, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Cooperative Behavior, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Psychiatric Status Rating Scales, Stress Disorders, Post-Traumatic, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10 000 cases and 30 000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration-of a scope that is unprecedented in the field of traumatic stress-will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD.

Published
2015

39. List of contributors

Author

Abdolmaleky, Hamid Mostafavi, primary, Akbarian, Schahram, additional, Ambrosini, Alexander, additional, Avramopoulos, Dimitrios, additional, Bendersky, Cari J., additional, Bendl, Jaroslav, additional, Bérubé, Nathalie G., additional, Bhat, Unis Ahmad, additional, Borreggine, Kristin, additional, Braun, Patricia R., additional, Brennand, Kristen J., additional, Castro, Amanda, additional, Chakravarty, Sumana, additional, Chang, Connie, additional, Cohen, Sophie, additional, Coppedè, Fabio, additional, Dahrendorff, Jan, additional, Dunn, Jeffrey T., additional, Eberwine, James H., additional, Elia, Josephine, additional, Fang, Gang, additional, Fels, Samuel, additional, Fernando, Michael B., additional, Franklin, Tamara Brook, additional, Fries, Gabriel R., additional, Frizzola, Meg, additional, Fullard, John F., additional, Ganguly, Sebanti, additional, Gapp, Katharina, additional, Garcia, Meilin Fernandez, additional, Gatta, Eleonora, additional, Grayson, Dennis R., additional, Gropman, Andrea L., additional, Guidotti, Alessandro, additional, Gupta, Praveer, additional, Hakonarson, Hakon, additional, Hunter, Richard G., additional, Imamura, Takuya, additional, Izaki, Yumiko, additional, Jakub, Taryn, additional, Keung, Crystal, additional, Kramer, Jamie M., additional, Kumar, Arvind, additional, Kundakovic, Marija, additional, Labonté, Benoit, additional, LaMarca, Elizabeth A., additional, Lee, Richard S., additional, Lima, Camila N.C., additional, Lutz, Pierre-Eric, additional, Matt, Stephanie M., additional, Milian, Allison A., additional, Miyashiro, Kevin Y., additional, Murgatroyd, Chris, additional, Nakashima, Kinichi, additional, Paul, Bidisha, additional, Peedicayil, Jacob, additional, Pinjari, Omar F., additional, Poddar, Karuna, additional, Potash, James B., additional, Powell, Samuel K., additional, Quesnel, Katerine, additional, Rayfield, Jessica, additional, Reddy, R. Gajendra, additional, Richter, Troy A., additional, Roth, Eric D., additional, Roth, Tania L., additional, Roussos, Panos, additional, Ruzicka, W. Brad, additional, Salarda, Erika M., additional, Santhosh, Samuel, additional, Saudagar, Vikram, additional, Stoccoro, Andrea, additional, Syed, Shariful A., additional, Thiagalingam, Sam, additional, Tollefsbol, Trygve O., additional, Turecki, Gustavo, additional, Uddin, Monica, additional, Uesaka, Masahiro, additional, Walker, Deena, additional, Yamamoto, Naoki, additional, Yost, Oliver, additional, and Zannas, Anthony S., additional

Published
2021
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41. Does biological age mediate the relationship between childhood adversity and depression? Insights from the Detroit Neighborhood Health Study

Author

Martinez, Rae Anne M., primary, Howard, Annie Green, additional, Fernández-Rhodes, Lindsay, additional, Maselko, Joanna, additional, Pence, Brian W., additional, Dhingra, Radhika, additional, Galea, Sandro, additional, Uddin, Monica, additional, Wildman, Derek E., additional, and Aiello, Allison E., additional

Published
2023
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42. 25. EPIGENOME-WIDE META-ANALYSIS OF > 3200 MILITARY AND CIVILIAN PARTICIPANTS IDENTIFIES CELL-TYPE SPECIFIC DNA METHYLATION SIGNALS ASSOCIATED WITH PTSD

Author

Katrinli, Seyma, primary, Wani, Agaz H., additional, Zhao, Xiang, additional, Maihofer, Adam X., additional, Zhao, Ying, additional, Nunez, Diana, additional, Montalvo-Ortiz, Janitza, additional, Zannas, Anthony S., additional, Logue, Mark, additional, Nievergelt, Caroline M., additional, Uddin, Monica, additional, and Smith, Alicia K., additional

Published
2023
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44. Current progress and future direction in the genetics of PTSD: Focus on the development and contributions of the PGC-PTSD working group

Author

Junglen, Angela G., primary, Sheerin, Christina, additional, Delahanty, Douglas L., additional, Hauser, Michael A., additional, Lori, Adriana, additional, Morey, Rajendra A., additional, Nievergelt, Caroline M., additional, Nugent, Nicole R., additional, Sebat, Jonathan, additional, Smith, Alicia K., additional, Sumner, Jennifer A., additional, Uddin, Monica, additional, and Amstadter, Ananda B., additional

Published
2020
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45. Traumatic stress and accelerated DNA methylation age: A meta-analysis

Author

Wolf, Erika J., Maniates, Hannah, Nugent, Nicole, Maihofer, Adam X., Armstrong, Don, Ratanatharathorn, Andrew, Ashley-Koch, Allison E., Garrett, Melanie, Kimbrel, Nathan A., Lori, Adriana, VA Mid-Atlantic MIRECC Workgroup, Aiello, Allison E., Baker, Dewleen G., Beckham, Jean C., Boks, Marco P., Galea, Sandro, Geuze, Elbert, Hauser, Michael A., Kessler, Ronald C., Koenen, Karestan C., Miller, Mark W., Ressler, Kerry J., Risbrough, Victoria, Rutten, Bart P.F., Stein, Murray B., Ursano, Robert J., Vermetten, Eric, Vinkers, Christiaan H., Uddin, Monica, Smith, Alicia K., Nievergelt, Caroline M., and Logue, Mark W.

Published
2018
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49. Research findings from nonpharmaceutical intervention studies for pandemic influenza and current gaps in the research

Author

Aiello, Allison E, Coulborn, Rebecca M, Aragon, Tomas J, Baker, Michael G, Burrus, Barri B, Cowling, Benjamin J, Duncan, Alasdair, Enanoria, Wayne, Fabian, M. Patricia, Ferng, Yu-hui, Larson, Elaine L, Leung, Gabriel M, Markel, Howard, Milton, Donald K, Monto, Arnold S, Morse, Stephen S, Navarro, J. Alexander, Park, Sarah Y, Priest, Patricia, Stebbins, Samuel, Stern, Alexandra M, Uddin, Monica, Wetterhall, Scott F, and Vukotich, Charles J

Published
2010

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