{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T18:13:09Z","timestamp":1788199989881,"version":"build-2803163510"},"reference-count":38,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2024,1,1]]},"abstract":"<jats:sec id=\"ab-yoi230083-4\"><jats:title>Importance<\/jats:title><jats:p>Posttraumatic stress disorder (PTSD) has been reported to be a risk factor for several physical and somatic symptoms. However, the genetics of PTSD and its potential association with medical outcomes remain unclear.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi230083-5\"><jats:title>Objective<\/jats:title><jats:p>To examine disease categories and laboratory tests from electronic health records (EHRs) that are associated with PTSD polygenic scores.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi230083-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This genetic association study was conducted from July 15, 2021, to January 24, 2023, using EHR data from participants across 4 biobanks. The polygenic scores of PTSD symptom severity (PGS-PTSD) were tested with all available phecodes in Vanderbilt University Medical Center\u2019s biobank (BioVU), Mass General Brigham (MGB), Michigan Genomics Initiative (MGI), and UK Biobank (UKBB). The significant medical outcomes were tested for overrepresented disease categories and subsequently tested for genetic correlation and 2-sample mendelian randomization (MR) to determine genetically informed associations. Multivariable MR was conducted to assess whether PTSD associations with health outcomes were independent of the genetic effect of body mass index and tobacco smoking.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi230083-7\"><jats:title>Exposures<\/jats:title><jats:p>Polygenic score of PTSD symptom severity.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi230083-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>A total of 1680 phecodes (ie, <jats:italic>International Classification of Diseases, Ninth Revision<\/jats:italic>\u2013 and <jats:italic>Tenth Revision<\/jats:italic>\u2013based phenotypic definitions of health outcomes) across 4 biobanks and 490 laboratory tests across 2 biobanks (BioVU and MGB).<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi230083-9\"><jats:title>Results<\/jats:title><jats:p>In this study including a total of 496\u202f317 individuals (mean [SD] age, 56.8 [8.0] years; 263\u202f048 female [53%]) across the 4 EHR sites, meta-analyzing associations of PGS-PTSD with 1680 phecodes from 496\u202f317 individuals showed significant associations to be overrepresented from mental health disorders (fold enrichment\u2009=\u20093.15; <jats:italic>P<\/jats:italic>\u2009=\u20095.81\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>), circulatory system (fold enrichment\u2009=\u20093.32; <jats:italic>P<\/jats:italic>\u2009=\u20096.39\u2009\u00d7\u200910<jats:sup>\u221212<\/jats:sup>), digestive (fold enrichment\u2009=\u20092.42; <jats:italic>P<\/jats:italic>\u2009=\u20092.16\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>), and respiratory outcomes (fold enrichment\u2009=\u20092.51; <jats:italic>P<\/jats:italic>\u2009=\u20098.28\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>). The laboratory measures scan with PGS-PTSD in BioVU and MGB biobanks revealed top associations in metabolic and immune domains. MR identified genetic liability to PTSD symptom severity as an associated risk factor for 12 health outcomes, including alcoholism (\u03b2\u2009=\u20090.023; <jats:italic>P<\/jats:italic>\u2009=\u20091.49\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>), tachycardia (\u03b2\u2009=\u20090.045; <jats:italic>P<\/jats:italic>\u2009=\u20098.30\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>), cardiac dysrhythmias (\u03b2\u2009=\u20090.016, <jats:italic>P<\/jats:italic>\u2009=\u20093.09\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>), and acute pancreatitis (\u03b2\u2009=\u20090.049, <jats:italic>P<\/jats:italic>\u2009=\u20094.48\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>). Several of these associations were robust to genetic effects of body mass index and smoking. We observed a bidirectional association between PTSD symptoms and nonspecific chest pain and C-reactive protein.<\/jats:p><\/jats:sec><jats:sec id=\"ab-yoi230083-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>Results of this study suggest the broad health repercussions associated with the genetic liability to PTSD across 4 biobanks. The circulatory and respiratory systems association was observed to be overrepresented in all 4 biobanks.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2023.4127","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T16:25:09Z","timestamp":1698855909000},"page":"34","source":"Crossref","is-referenced-by-count":18,"title":["Genetic Liability to Posttraumatic Stress Disorder Symptoms and Its Association With Cardiometabolic and Respiratory Outcomes"],"prefix":"10.1001","volume":"81","author":[{"given":"Gita A.","family":"Pathak","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut"},{"name":"Veteran Affairs Connecticut Healthcare Center, West Haven"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kritika","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karmel W.","family":"Choi","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston"},{"name":"Department of Psychiatry, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Fang","sequence":"additional","affiliation":[{"name":"Michigan Neuroscience Institute, University of Michigan, Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela R.","family":"Kouakou","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut"},{"name":"Veteran Affairs Connecticut Healthcare Center, West Haven"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Younga Heather","family":"Lee","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston"},{"name":"Department of Psychiatry, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, University of Michigan Medicine, Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars G.","family":"Fritsche","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, University of Michigan Medicine, Ann Arbor"},{"name":"Rogel Cancer Center, University of Michigan Medicine, Ann Arbor"},{"name":"Center for Statistical Genetics, School of Public Health, University of Michigan Medicine, Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R.","family":"Wendt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut"},{"name":"Veteran Affairs Connecticut Healthcare Center, West Haven"},{"name":"Department of Anthropology, University of Toronto, Mississauga, Ontario, Canada"},{"name":"Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea K.","family":"Davis","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Polimanti","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut"},{"name":"Veteran Affairs Connecticut Healthcare Center, West Haven"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"3","key":"yoi230083r1","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1038\/s41380-022-01488-9","article-title":"Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardiometabolic traits.","volume":"27","author":"Pathak","year":"2022","journal-title":"Mol Psychiatry"},{"issue":"13","key":"yoi230083r2","doi-asserted-by":"publisher","first-page":"2260","DOI":"10.1017\/S0033291717000708","article-title":"Posttraumatic stress disorder in the World Mental Health Surveys.","volume":"47","author":"Koenen","year":"2017","journal-title":"Psychol Med"},{"issue":"2","key":"yoi230083r3","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/s41588-020-00767-x","article-title":"Genome-wide association analyses of posttraumatic stress disorder and its symptom subdomains in the Million Veteran Program.","volume":"53","author":"Stein","year":"2021","journal-title":"Nat Genet"},{"issue":"1","key":"yoi230083r4","doi-asserted-by":"publisher","first-page":"4558","DOI":"10.1038\/s41467-019-12576-w","article-title":"International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.","volume":"10","author":"Nievergelt","year":"2019","journal-title":"Nat Commun"},{"issue":"1 Pt 1","key":"yoi230083r5","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ygeno.2020.11.032","article-title":"Characterizing the effect of background selection on the polygenicity of brain-related traits.","volume":"113","author":"Wendt","year":"2021","journal-title":"Genomics"},{"issue":"11","key":"yoi230083r6","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1176\/appi.ajp.20220795","article-title":"Polygenic scores in psychiatry: on the road from discovery to implementation.","volume":"179","author":"Lewis","year":"2022","journal-title":"Am J Psychiatry"},{"issue":"1","key":"yoi230083r7","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1001\/jamapsychiatry.2020.3049","article-title":"From basic science to clinical application of polygenic risk scores: a primer.","volume":"78","author":"Wray","year":"2021","journal-title":"JAMA Psychiatry"},{"issue":"7","key":"yoi230083r8","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/j.biopsych.2021.09.020","article-title":"Enhancing discovery of genetic variants for posttraumatic stress disorder through integration of quantitative phenotypes and trauma exposure information.","volume":"91","author":"Maihofer","year":"2022","journal-title":"Biol Psychiatry"},{"issue":"1","key":"yoi230083r9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.janxdis.2012.08.004","article-title":"The physical health consequences of PTSD and PTSD symptoms: a meta-analytic review.","volume":"27","author":"Pacella","year":"2013","journal-title":"J Anxiety Disord"},{"issue":"1","key":"yoi230083r10","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1038\/s41467-019-09718-5","article-title":"Polygenic prediction via Bayesian regression and continuous shrinkage priors.","volume":"10","author":"Ge","year":"2019","journal-title":"Nat Commun"},{"issue":"16","key":"yoi230083r11","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1093\/bioinformatics\/btu197","article-title":"R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment.","volume":"30","author":"Carroll","year":"2014","journal-title":"Bioinformatics"},{"issue":"1","key":"yoi230083r12","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13073-020-00820-8","article-title":"Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease.","volume":"13","author":"Dennis","year":"2021","journal-title":"Genome Med"},{"issue":"3","key":"yoi230083r13","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"key":"yoi230083r14","doi-asserted-by":"publisher","first-page":"7","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome.","volume":"7","author":"Hemani","year":"2018","journal-title":"Elife"},{"issue":"1","key":"yoi230083r15","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1097\/EDE.0000000000000559","article-title":"Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants.","volume":"28","author":"Burgess","year":"2017","journal-title":"Epidemiology"},{"issue":"2","key":"yoi230083r16","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"issue":"1","key":"yoi230083r18","doi-asserted-by":"publisher","first-page":"5302","DOI":"10.1038\/s41467-020-18489-3","article-title":"Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals.","volume":"11","author":"Xu","year":"2020","journal-title":"Nat Commun"},{"issue":"25","key":"yoi230083r19","doi-asserted-by":"publisher","first-page":"5434","DOI":"10.1002\/sim.v40.25","article-title":"Testing and correcting for weak and pleiotropic instruments in 2-sample multivariable mendelian randomization.","volume":"40","author":"Sanderson","year":"2021","journal-title":"Stat Med"},{"issue":"5","key":"yoi230083r20","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1007\/s00406-021-01342-z","article-title":"Co-occurrence of severe PTSD, somatic symptoms and dissociation in a large sample of childhood trauma inpatients: a network analysis.","volume":"272","author":"Kratzer","year":"2022","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"issue":"11","key":"yoi230083r21","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1176\/appi.ajp.21111113","article-title":"Leveraging large-scale genetics of PTSD and cardiovascular disease to demonstrate robust shared risk and improve risk prediction accuracy.","volume":"179","author":"Seligowski","year":"2022","journal-title":"Am J Psychiatry"},{"key":"yoi230083r22","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/5599265","article-title":"New metabolic, digestive, and oxidative stress-related manifestations associated with posttraumatic stress disorder.","volume":"2021","author":"Oroian","year":"2021","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"yoi230083r23","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3109\/09540261.2012.736367","article-title":"Review of somatic symptoms in posttraumatic stress disorder.","volume":"25","author":"Gupta","year":"2013","journal-title":"Int Rev Psychiatry"},{"issue":"3","key":"yoi230083r24","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1097\/EDE.0000000000000622","article-title":"Posttraumatic stress disorder and gastrointestinal disorders in the Danish population.","volume":"28","author":"Gradus","year":"2017","journal-title":"Epidemiology"},{"issue":"12","key":"yoi230083r25","doi-asserted-by":"publisher","first-page":"4109","DOI":"10.1007\/s10620-020-06798-y","article-title":"Prevalence and impact of posttraumatic stress disorder in gastrointestinal conditions: a systematic review.","volume":"66","author":"Glynn","year":"2021","journal-title":"Dig Dis Sci"},{"key":"yoi230083r26","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fphys.2015.00012","article-title":"The regulation of muscle mass by endogenous glucocorticoids.","volume":"6","author":"Braun","year":"2015","journal-title":"Front Physiol"},{"issue":"1","key":"yoi230083r27","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1186\/s13063-018-2753-x","article-title":"The impact of an exercise training intervention on cortisol levels and posttraumatic stress disorder in juveniles from an Ugandan refugee settlement: study protocol for a randomized control trial.","volume":"19","author":"Budde","year":"2018","journal-title":"Trials"},{"issue":"12","key":"yoi230083r28","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.1210\/en.2011-1218","article-title":"Minireview: stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis.","volume":"152","author":"Yehuda","year":"2011","journal-title":"Endocrinology"},{"issue":"6","key":"yoi230083r29","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1038\/s41386-020-0655-6","article-title":"Dissecting the genetic association of C-reactive protein with PTSD, traumatic events, and social support.","volume":"46","author":"Muniz Carvalho","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"yoi230083r30","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.bbi.2019.10.021","article-title":"Symptom severity impacts sympathetic dysregulation and inflammation in posttraumatic stress disorder (PTSD).","volume":"83","author":"Fonkoue","year":"2020","journal-title":"Brain Behav Immun"},{"issue":"4","key":"yoi230083r31","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/S2215-0366(16)30377-7","article-title":"Posttraumatic stress disorder and cardiovascular disease.","volume":"4","author":"Edmondson","year":"2017","journal-title":"Lancet Psychiatry"},{"issue":"11","key":"yoi230083r32","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1038\/s41593-022-01161-y","article-title":"Modeling gene \u00d7 environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression.","volume":"25","author":"Seah","year":"2022","journal-title":"Nat Neurosci"},{"issue":"7","key":"yoi230083r33","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.biopsych.2022.09.033","article-title":"Stem cell models for context-specific modeling in psychiatric disorders.","volume":"93","author":"Seah","year":"2023","journal-title":"Biol Psychiatry"},{"issue":"1","key":"yoi230083r34","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/s41398-019-0539-x","article-title":"Differential transcriptional response following glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development.","volume":"9","author":"Breen","year":"2019","journal-title":"Transl Psychiatry"},{"issue":"12","key":"yoi230083r36","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1001\/jamapsychiatry.2021.2959","article-title":"Use of the PsycheMERGE Network to investigate the association between depression polygenic scores and white blood cell count.","volume":"78","author":"Sealock","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"yoi230083r17","unstructured":"GIANT consortium. GIANT: genetic investigation of anthropometric traits. Accessed January 8, 2023. https:\/\/portals.broadinstitute.org\/collaboration\/giant\/index.php\/GIANT_consortium"},{"key":"yoi230083r35","unstructured":"Genes associated with depression and coronary artery disease are enriched for inflammation and cardiomyopathy-associated pathways.? medRxiv. 2022."},{"key":"yoi230083r37","unstructured":"Andrew? DG, Kritika? S, Tyne? WM-F, . T-SEM of 11 major psychiatric disorders: identification of gene expression patterns for cross-disorder risk and drug repurposing.? medRxiv. 2022:2022.2011.2001.22281811."},{"key":"yoi230083r38","unstructured":"Jiayue-Clara? J, Kritika? S, Lea? KD, Naomi? RW, Sonia? S. A higher genetic risk for depression is a greater risk factor for cardiovascular disease in women.? medRxiv. 2023:2022.2010.2008.22280805."}],"container-title":["JAMA Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamapsychiatry\/articlepdf\/2811150\/jamapsychiatry_pathak_2023_oi_230083_1703694727.80002.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T16:03:09Z","timestamp":1704297789000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamapsychiatry\/fullarticle\/2811150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,1]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamapsychiatry.2023.4127","relation":{},"ISSN":["2168-622X"],"issn-type":[{"value":"2168-622X","type":"print"}],"subject":[],"published":{"date-parts":[[2024,1,1]]}}}