{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:26:21Z","timestamp":1793316381339,"version":"4.5.0"},"posted":{"date-parts":[[2023,3,25]]},"group-title":"Genetic and Genomic Medicine","reference-count":59,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Many psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans\u2019 health, such as suicide-related behaviors, substance use disorders, and other medical conditions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (\n                    <jats:italic>N<\/jats:italic>\n                    = 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic\/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family analysis of significant associations from the main PheWAS in full-siblings (N = 12,127, European ancestries only).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The EXT PGS was associated with 619 outcomes across all bodily systems, of which, 188 were independent of risk for comorbid problems of PGS. Effect sizes ranged from OR = 1.02 (95% CI = 1.01, 1.03) for overweight\/obesity to OR = 1.44 (95% CI = 1.42, 1.47) for viral hepatitis C. Of the significant outcomes 73 (11.9%) and 26 (4.5%) were significant in the African and Hispanic\/Latin American results, respectively. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including liver disease, chronic airway obstruction, and viral hepatitis C.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and independent of risk for other psychiatric problems. The strongest associations with EXT were for diagnoses related to substance use disorders and their sequelae. Overall, we highlight the potential negative consequences of EXT for health and functioning in the US veteran population.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.03.22.23286865","type":"posted-content","created":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T18:05:14Z","timestamp":1679767514000},"source":"Crossref","is-referenced-by-count":2,"title":["Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9321-657X","authenticated-orcid":false,"given":"Peter B.","family":"Barr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2215-5946","authenticated-orcid":false,"given":"Tim B.","family":"Bigdeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-8555","authenticated-orcid":false,"given":"Jacquelyn L.","family":"Meyers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-849X","authenticated-orcid":false,"given":"Roseann E.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6137-5699","authenticated-orcid":false,"given":"Sandra","family":"Sanchez-Roige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-3001","authenticated-orcid":false,"given":"Travis T.","family":"Mallard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1636-893X","authenticated-orcid":false,"given":"Danielle M.","family":"Dick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-6737","authenticated-orcid":false,"given":"K. Paige","family":"Harden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5798-1335","authenticated-orcid":false,"given":"David P.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Swann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele K.","family":"Lipsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-555X","authenticated-orcid":false,"given":"Thomas","family":"Kosten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Aslan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9501-9366","authenticated-orcid":false,"given":"Philip D.","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7218-1005","authenticated-orcid":false,"given":"Nathan A.","family":"Kimbrel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8746-8949","authenticated-orcid":false,"given":"Jean C.","family":"Beckham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023071307401327000_2023.03.22.23286865v3.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(21)00395-3"},{"key":"2023071307401327000_2023.03.22.23286865v3.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.0158"},{"issue":"10082","key":"2023071307401327000_2023.03.22.23286865v3.3","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1016\/S0140-6736(17)30819-X","article-title":"Smoking prevalence and attributable disease burden in 195 countries and territories, 1990\u20132015: a systematic analysis from the Global Burden of Disease Study 2015","volume":"389","year":"2017","journal-title":"The Lancet"},{"key":"2023071307401327000_2023.03.22.23286865v3.4","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(18)30337-7"},{"key":"2023071307401327000_2023.03.22.23286865v3.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap8757"},{"key":"2023071307401327000_2023.03.22.23286865v3.6","doi-asserted-by":"publisher","DOI":"10.1037\/h0092976"},{"key":"2023071307401327000_2023.03.22.23286865v3.7","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291722001301"},{"key":"2023071307401327000_2023.03.22.23286865v3.8","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.61.9.922"},{"key":"2023071307401327000_2023.03.22.23286865v3.9","doi-asserted-by":"publisher","DOI":"10.1037\/0021-843X.111.3.411"},{"key":"2023071307401327000_2023.03.22.23286865v3.10","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2019_120"},{"key":"2023071307401327000_2023.03.22.23286865v3.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00908-3"},{"key":"2023071307401327000_2023.03.22.23286865v3.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsgos.2021.09.007"},{"key":"2023071307401327000_2023.03.22.23286865v3.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2021.05.029"},{"key":"2023071307401327000_2023.03.22.23286865v3.14","doi-asserted-by":"publisher","DOI":"10.1159\/000517169"},{"key":"2023071307401327000_2023.03.22.23286865v3.15","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.06.23286866"},{"key":"2023071307401327000_2023.03.22.23286865v3.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09480-8"},{"key":"2023071307401327000_2023.03.22.23286865v3.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0416-1"},{"key":"2023071307401327000_2023.03.22.23286865v3.18","doi-asserted-by":"publisher","DOI":"10.1111\/add.15697"},{"key":"2023071307401327000_2023.03.22.23286865v3.19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1809937"},{"key":"2023071307401327000_2023.03.22.23286865v3.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"2023071307401327000_2023.03.22.23286865v3.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8"},{"key":"2023071307401327000_2023.03.22.23286865v3.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.je.2016.12.005"},{"key":"2023071307401327000_2023.03.22.23286865v3.23","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq126"},{"key":"2023071307401327000_2023.03.22.23286865v3.24","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2019.18091085"},{"key":"2023071307401327000_2023.03.22.23286865v3.25","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2022.2742"},{"key":"2023071307401327000_2023.03.22.23286865v3.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2015.09.016"},{"key":"2023071307401327000_2023.03.22.23286865v3.27","doi-asserted-by":"publisher","DOI":"10.1016\/J.EURONEURO.2017.06.069"},{"key":"2023071307401327000_2023.03.22.23286865v3.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04434-5"},{"key":"2023071307401327000_2023.03.22.23286865v3.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0326-7"},{"key":"2023071307401327000_2023.03.22.23286865v3.30","unstructured":"Kramarow EA , Pastor PN . The health of male veterans and nonveterans aged 25-64: United States, 2007-2010. NCHS Data Brief. 2012;(101):1\u20138."},{"key":"2023071307401327000_2023.03.22.23286865v3.31","doi-asserted-by":"crossref","unstructured":"Boersma P , Cohen RA , Zelaya CE , Moy E . Multiple Chronic Conditions Among Veterans and Nonveterans: United States, 2015-2018. Natl Health Stat Report. 2021;(153):1\u201313. Accessed March 28, 2022. https:\/\/europepmc.org\/article\/med\/33663648","DOI":"10.15620\/cdc:101659"},{"key":"2023071307401327000_2023.03.22.23286865v3.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.03.004"},{"key":"2023071307401327000_2023.03.22.23286865v3.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.08.012"},{"key":"2023071307401327000_2023.03.22.23286865v3.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03205-y"},{"key":"2023071307401327000_2023.03.22.23286865v3.35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008500"},{"key":"2023071307401327000_2023.03.22.23286865v3.36","doi-asserted-by":"publisher","DOI":"10.1177\/0022146510383838"},{"key":"2023071307401327000_2023.03.22.23286865v3.37","doi-asserted-by":"publisher","DOI":"10.1007\/s10865-008-9185-0"},{"key":"2023071307401327000_2023.03.22.23286865v3.38","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2749"},{"key":"2023071307401327000_2023.03.22.23286865v3.39","doi-asserted-by":"publisher","DOI":"10.2196\/10788"},{"key":"2023071307401327000_2023.03.22.23286865v3.40","doi-asserted-by":"publisher","DOI":"10.1093\/jamia\/ocv130"},{"key":"2023071307401327000_2023.03.22.23286865v3.41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175508"},{"key":"2023071307401327000_2023.03.22.23286865v3.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"2023071307401327000_2023.03.22.23286865v3.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06079-4"},{"key":"2023071307401327000_2023.03.22.23286865v3.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01054-7"},{"key":"2023071307401327000_2023.03.22.23286865v3.45","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.39702"},{"key":"2023071307401327000_2023.03.22.23286865v3.46","unstructured":"Stammann A , Heiss F , McFadden D . Estimating Fixed Effects Logit Models with Large Panel Data. In: Beitr\u00e4ge Zur Jahrestagung Des Vereins F\u00fcr Socialpolitik 2016: Demographischer Wandel - Session: Microeconometrics, No. G01-V3. Beitr\u00e4ge zur Jahrestagung des Vereins f\u00fcr Socialpolitik 2016: Demographischer Wandel - Session: Microeconometrics. ZBW - Deutsche Zentralbibliothek f\u00fcr Wirtschaftswissenschaften, Leibniz-Informationszentrum Wirtschaft; 2016:1\u201340. http:\/\/hdl.handle.net\/10419\/145837"},{"key":"2023071307401327000_2023.03.22.23286865v3.47","doi-asserted-by":"publisher","DOI":"10.2307\/2346101"},{"key":"2023071307401327000_2023.03.22.23286865v3.48","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx364"},{"key":"2023071307401327000_2023.03.22.23286865v3.49","doi-asserted-by":"publisher","DOI":"10.1109\/TVCG.2014.2346248"},{"key":"2023071307401327000_2023.03.22.23286865v3.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01801-6"},{"key":"2023071307401327000_2023.03.22.23286865v3.51","doi-asserted-by":"publisher","DOI":"10.5498\/WJP.V5.I3.255"},{"key":"2023071307401327000_2023.03.22.23286865v3.52","doi-asserted-by":"publisher","DOI":"10.1101\/2021.07.16.452740"},{"key":"2023071307401327000_2023.03.22.23286865v3.53","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00763-0"},{"key":"2023071307401327000_2023.03.22.23286865v3.54","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2020.3049"},{"key":"2023071307401327000_2023.03.22.23286865v3.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-020-00865-8"},{"key":"2023071307401327000_2023.03.22.23286865v3.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0379-x"},{"key":"2023071307401327000_2023.03.22.23286865v3.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0546-6"},{"key":"2023071307401327000_2023.03.22.23286865v3.58","doi-asserted-by":"publisher","DOI":"10.1111\/jcpp.13664"},{"key":"2023071307401327000_2023.03.22.23286865v3.59","doi-asserted-by":"publisher","DOI":"10.4088\/PCC.18m02350"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.03.22.23286865","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:30:24Z","timestamp":1768505424000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.03.22.23286865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,25]]},"references-count":59,"URL":"https:\/\/doi.org\/10.1101\/2023.03.22.23286865","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1001\/jamapsychiatry.2023.4141","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,3,25]]},"subtype":"preprint"}}