{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:44:03Z","timestamp":1793040243097,"version":"4.5.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2025671"],"award-info":[{"award-number":["2025671"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT2018420"],"award-info":[{"award-number":["GNT2018420"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2034743"],"award-info":[{"award-number":["2034743"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2027002"],"award-info":[{"award-number":["2027002"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"Department of Health | National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2026364"],"award-info":[{"award-number":["2026364"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Genet"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Major depressive disorder (MDD) is characterized by substantial comorbidity with medical conditions. To achieve better outcomes for patients with MDD, an improved understanding of the mechanisms underlying pervasive comorbidities is required. Here, to this end, we mapped patterns of pleiotropy by defining four clusters of physical diseases (cardiovascular, metabolic, gastrointestinal and immune) and analyzed their genetic relationships with MDD using genomic structural equation modeling. Three disease clusters exhibited independent associations with MDD and accounted for 47% of MDD\n                    <jats:italic>h<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sub>SNP<\/jats:sub>\n                    , with the gastrointestinal disease cluster having the strongest association (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20090.63, s.e.\u2009=\u20090.05,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20093.04\u2009\u00d7\u200910\n                    <jats:sup>\u221230<\/jats:sup>\n                    ). In addition, we identified independent loci associated with the shared genetic liability between each disease cluster and MDD, revealing different pleiotropic components. Characterization of these loci revealed previously unidentified associations with MDD and physical disease traits, along with unique biological pathways, drug groups, cell types and genes associated with each disease\u2013MDD cluster. Our findings reveal genetic connections implicating the gut\u2013brain axis as a key mechanism underlying the comorbidity of physical diseases in MDD. This work advances our understanding of MDD by highlighting unique and shared genetic components across different disease systems.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02735-3","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:03:08Z","timestamp":1787734988000},"page":"2201-2210","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dissecting pleiotropy between major depressive disorder and physical disease comorbidities"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1244-6977","authenticated-orcid":false,"given":"Damian J.","family":"Woodward","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7689-2453","authenticated-orcid":false,"given":"William R.","family":"Reay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1645-6307","authenticated-orcid":false,"given":"Briar","family":"Wormington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Diaz-Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue-Sheng","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2445-1266","authenticated-orcid":false,"given":"Zachary F.","family":"Gerring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-6417","authenticated-orcid":false,"given":"Jackson G.","family":"Thorp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eske M.","family":"Derks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"2735_CR1","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jad.2014.10.010","volume":"172","author":"EI Fried","year":"2015","unstructured":"Fried, E. I. & Nesse, R. M. Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. J. Affect. Disord. 172, 96\u2013102 (2015).","journal-title":"J. Affect. Disord."},{"key":"2735_CR2","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/S2215-0366(21)00395-3","volume":"9","author":"GBD 2019 Mental Disorders Collaborators","year":"2022","unstructured":"GBD 2019 Mental Disorders Collaborators Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u20132019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry 9, 137\u2013150 (2022).","journal-title":"Lancet Psychiatry"},{"key":"2735_CR3","doi-asserted-by":"publisher","DOI":"10.1192\/bjo.2022.583","volume":"8","author":"N Weye","year":"2022","unstructured":"Weye, N. et al. The contribution of general medical conditions to the non-fatal burden of mental disorders: register-based cohort study in Denmark. BJPsych Open 8, e180 (2022).","journal-title":"BJPsych Open"},{"key":"2735_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0200-2","volume":"6","author":"SM Gold","year":"2020","unstructured":"Gold, S. M. et al. Comorbid depression in medical diseases. Nat. Rev. Dis. Primers 6, 69 (2020).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"2735_CR5","doi-asserted-by":"publisher","first-page":"2398","DOI":"10.2337\/dc08-1341","volume":"31","author":"JS Gonzalez","year":"2008","unstructured":"Gonzalez, J. S. et al. Depression and diabetes treatment nonadherence: a meta-analysis. Diabetes Care 31, 2398\u20132403 (2008).","journal-title":"Diabetes Care"},{"key":"2735_CR6","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1007\/s11606-011-1704-y","volume":"26","author":"JL Grenard","year":"2011","unstructured":"Grenard, J. L. et al. Depression and medication adherence in the treatment of chronic diseases in the United States: a meta-analysis. J. Gen. Intern. Med. 26, 1175\u20131182 (2011).","journal-title":"J. Gen. Intern. Med."},{"key":"2735_CR7","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1017\/S1041610214000611","volume":"26","author":"CS Ho","year":"2014","unstructured":"Ho, C. S. et al. Coexisting medical comorbidity and depression: multiplicative effects on health outcomes in older adults. Int. Psychogeriatr. 26, 1221\u20131229 (2014).","journal-title":"Int. Psychogeriatr."},{"key":"2735_CR8","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1111\/acps.12899","volume":"138","author":"A Koyanagi","year":"2018","unstructured":"Koyanagi, A. et al. Mortality in unipolar depression preceding and following chronic somatic diseases. Acta Psychiatr. Scand. 138, 500\u2013508 (2018).","journal-title":"Acta Psychiatr. Scand."},{"key":"2735_CR9","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-014-0371-z","volume":"14","author":"Y Gan","year":"2014","unstructured":"Gan, Y. et al. Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC Psychiatry 14, 371 (2014).","journal-title":"BMC Psychiatry"},{"key":"2735_CR10","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1002\/gps.1723","volume":"22","author":"K Van der Kooy","year":"2007","unstructured":"Van der Kooy, K. et al. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int. J. Geriatr. Psychiatry 22, 613\u2013626 (2007).","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"2735_CR11","doi-asserted-by":"publisher","first-page":"e14596","DOI":"10.1097\/MD.0000000000014596","volume":"98","author":"L Feng","year":"2019","unstructured":"Feng, L. et al. Prevalence of depression in myocardial infarction: a PRISMA-compliant meta-analysis. Medicine 98, e14596 (2019).","journal-title":"Medicine"},{"key":"2735_CR12","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1002\/wps.20420","volume":"16","author":"CU Correll","year":"2017","unstructured":"Correll, C. U. et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry 16, 163\u2013180 (2017).","journal-title":"World Psychiatry"},{"key":"2735_CR13","doi-asserted-by":"publisher","DOI":"10.5812\/ircmj.26523","volume":"18","author":"R Ghanei Gheshlagh","year":"2016","unstructured":"Ghanei Gheshlagh, R., Parizad, N. & Sayehmiri, K. The relationship between depression and metabolic syndrome: systematic review and meta-analysis study. Iran Red Crescent Med. J. 18, e26523 (2016).","journal-title":"Iran Red Crescent Med. J."},{"key":"2735_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pcd.2021.11.001","volume":"16","author":"A Farooqi","year":"2022","unstructured":"Farooqi, A. et al. A systematic review and meta-analysis to compare the prevalence of depression between people with and without type 1 and type 2 diabetes. Prim. Care Diabetes 16, 1\u201310 (2022).","journal-title":"Prim. Care Diabetes"},{"key":"2735_CR15","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.4525","volume":"7","author":"C Chourpiliadis","year":"2024","unstructured":"Chourpiliadis, C. et al. Metabolic profile and long-term risk of depression, anxiety, and stress-related disorders. JAMA Netw. Open 7, e244525 (2024).","journal-title":"JAMA Netw. Open"},{"key":"2735_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2020.110209","volume":"107","author":"H Person","year":"2021","unstructured":"Person, H. & Keefer, L. Psychological comorbidity in gastrointestinal diseases: update on the brain\u2013gut\u2013microbiome axis. Prog. Neuropsychopharmacol. Biol. Psychiatry 107, 110209 (2021).","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"2735_CR17","doi-asserted-by":"publisher","first-page":"349","DOI":"10.5056\/jnm16220","volume":"23","author":"C Lee","year":"2017","unstructured":"Lee, C. et al. The increased level of depression and anxiety in irritable bowel syndrome patients compared with healthy controls: systematic review and meta-analysis. J. Neurogastroenterol. Motil. 23, 349\u2013362 (2017).","journal-title":"J. Neurogastroenterol. Motil."},{"key":"2735_CR18","doi-asserted-by":"publisher","first-page":"e2333","DOI":"10.1097\/MD.0000000000002333","volume":"94","author":"C-C Hsu","year":"2015","unstructured":"Hsu, C.-C. et al. Depression and the risk of peptic ulcer disease. Medicine 94, e2333 (2015).","journal-title":"Medicine"},{"key":"2735_CR19","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/j.bbi.2020.02.010","volume":"87","author":"EF Osimo","year":"2020","unstructured":"Osimo, E. F. et al. Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav. Immun. 87, 901\u2013909 (2020).","journal-title":"Brain Behav. Immun."},{"key":"2735_CR20","doi-asserted-by":"publisher","first-page":"3559","DOI":"10.1017\/S0033291715001488","volume":"45","author":"NW Andersson","year":"2015","unstructured":"Andersson, N. W. et al. Depression and the risk of autoimmune disease: a nationally representative, prospective longitudinal study. Psychol. Med. 45, 3559\u20133569 (2015).","journal-title":"Psychol. Med."},{"key":"2735_CR21","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.1038\/s41591-023-02352-1","volume":"29","author":"TD Als","year":"2023","unstructured":"Als, T. D. et al. Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses. Nat. Med. 29, 1832\u20131844 (2023).","journal-title":"Nat. Med."},{"key":"2735_CR22","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/s44161-024-00488-y","volume":"3","author":"J Bergstedt","year":"2024","unstructured":"Bergstedt, J. et al. Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease. Nat. Cardiovasc. Res. 3, 754\u2013769 (2024).","journal-title":"Nat. Cardiovasc. Res."},{"key":"2735_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-024-02759-5","volume":"14","author":"X Gao","year":"2024","unstructured":"Gao, X. et al. Genetic evidence for the causal relations between metabolic syndrome and psychiatric disorders: a Mendelian randomization study. Transl. Psychiatry 14, 46 (2024).","journal-title":"Transl. Psychiatry"},{"key":"2735_CR24","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1001\/jamapsychiatry.2022.4974","volume":"80","author":"W Gong","year":"2023","unstructured":"Gong, W. et al. Role of the gut\u2013brain axis in the shared genetic etiology between gastrointestinal tract diseases and psychiatric disorders: a genome-wide pleiotropic analysis. JAMA Psychiatry 80, 360 (2023).","journal-title":"JAMA Psychiatry"},{"key":"2735_CR25","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1001\/jamapsychiatry.2022.0914","volume":"79","author":"DS Tylee","year":"2022","unstructured":"Tylee, D. S. et al. An atlas of genetic correlations and genetically informed associations linking psychiatric and immune-related phenotypes. JAMA Psychiatry 79, 667\u2013676 (2022).","journal-title":"JAMA Psychiatry"},{"key":"2735_CR26","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","volume":"627","author":"K Suzuki","year":"2024","unstructured":"Suzuki, K. et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature 627, 347\u2013357 (2024).","journal-title":"Nature"},{"key":"2735_CR27","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s41562-019-0566-x","volume":"3","author":"AD Grotzinger","year":"2019","unstructured":"Grotzinger, A. D. et al. Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits. Nat. Hum. Behav. 3, 513\u2013525 (2019).","journal-title":"Nat. Hum. Behav."},{"key":"2735_CR28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041640","volume":"22","author":"K Suneson","year":"2021","unstructured":"Suneson, K., Lindahl, J., Chamli H\u00e5rsmar, S., S\u00f6derberg, G. & Lindqvist, D. Inflammatory depression\u2014mechanisms and non-pharmacological interventions. Int. J. Mol. Sci. 22, 1640 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"2735_CR29","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1002\/wps.21110","volume":"22","author":"M Berk","year":"2023","unstructured":"Berk, M. et al. Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management. World Psychiatry 22, 366\u2013387 (2023).","journal-title":"World Psychiatry"},{"key":"2735_CR30","doi-asserted-by":"publisher","first-page":"D1311","DOI":"10.1093\/nar\/gkaa840","volume":"49","author":"M Ghoussaini","year":"2021","unstructured":"Ghoussaini, M. et al. Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics. Nucleic Acids Res. 49, D1311\u2013D1320 (2021).","journal-title":"Nucleic Acids Res."},{"key":"2735_CR31","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-023-04333-9","volume":"38","author":"L Yan","year":"2023","unstructured":"Yan, L. et al. The role of psychological factors in functional gastrointestinal disorders: a systematic review and meta-analysis. Int. J. Colorectal Dis. 38, 65 (2023).","journal-title":"Int. J. Colorectal Dis."},{"key":"2735_CR32","doi-asserted-by":"publisher","first-page":"44","DOI":"10.7861\/clinmed.2020-0980","volume":"21","author":"A Fikree","year":"2021","unstructured":"Fikree, A. & Byrne, P. Management of functional gastrointestinal disorders. Clin. Med. 21, 44\u201352 (2021).","journal-title":"Clin. Med."},{"key":"2735_CR33","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1136\/gutjnl-2020-323906","volume":"71","author":"J-S Ong","year":"2022","unstructured":"Ong, J.-S. et al. Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett\u2019s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis. Gut 71, 1053\u20131061 (2022).","journal-title":"Gut"},{"key":"2735_CR34","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1038\/s41588-018-0255-0","volume":"50","author":"LJ O\u2019Connor","year":"2018","unstructured":"O\u2019Connor, L. J. & Price, A. L. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat. Genet. 50, 1728\u20131734 (2018).","journal-title":"Nat. Genet."},{"key":"2735_CR35","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1038\/s41588-020-0631-4","volume":"52","author":"J Morrison","year":"2020","unstructured":"Morrison, J., Knoblauch, N., Marcus, J. H., Stephens, M. & He, X. Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat. Genet. 52, 740\u2013747 (2020).","journal-title":"Nat. Genet."},{"key":"2735_CR36","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1038\/s41588-024-01771-1","volume":"56","author":"O Frei","year":"2024","unstructured":"Frei, O. et al. Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nat. Genet. 56, 1310\u20131318 (2024).","journal-title":"Nat. Genet."},{"key":"2735_CR37","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/ng.3506","volume":"48","author":"A Gusev","year":"2016","unstructured":"Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245\u2013252 (2016).","journal-title":"Nat. Genet."},{"key":"2735_CR38","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.ajhg.2019.01.002","volume":"104","author":"Y Liu","year":"2019","unstructured":"Liu, Y. et al. ACAT: a fast and powerful P value combination method for rare-variant analysis in sequencing studies. Am. J. Hum. Genet. 104, 410\u2013421 (2019).","journal-title":"Am. J. Hum. Genet."},{"key":"2735_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1274595","volume":"10","author":"X Li","year":"2023","unstructured":"Li, X., Zhou, J., Wang, M., Yang, C. & Sun, G. Cardiovascular disease and depression: a narrative review. Front. Cardiovasc. Med. 10, 1274595 (2023).","journal-title":"Front. Cardiovasc. Med."},{"key":"2735_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2024.101166","volume":"48","author":"BWJH Penninx","year":"2024","unstructured":"Penninx, B. W. J. H. et al. Immuno-metabolic depression: from concept to implementation. Lancet Reg. Health Eur. 48, 101166 (2024).","journal-title":"Lancet Reg. Health Eur."},{"key":"2735_CR41","volume":"16","author":"A Singh","year":"2024","unstructured":"Singh, A., Kishore, P. S. & Khan, S. From microbes to myocardium: a comprehensive review of the impact of the gut\u2013brain axis on cardiovascular disease. Cureus 16, e70877 (2024).","journal-title":"Cureus"},{"key":"2735_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12020-023-03640-z","volume":"84","author":"Y Pan","year":"2024","unstructured":"Pan, Y., Bu, T., Deng, X., Jia, J. & Yuan, G. Gut microbiota and type 2 diabetes mellitus: a focus on the gut\u2013brain axis. Endocrine 84, 1\u201315 (2024).","journal-title":"Endocrine"},{"key":"2735_CR43","doi-asserted-by":"publisher","DOI":"10.3390\/nu16030390","volume":"16","author":"A Dos Santos","year":"2024","unstructured":"Dos Santos, A. & Gali\u00e8, S. The microbiota\u2013gut\u2013brain axis in metabolic syndrome and sleep disorders: a systematic review. Nutrients 16, 390 (2024).","journal-title":"Nutrients"},{"key":"2735_CR44","first-page":"e48655","volume":"15","author":"MMSr Khawar","year":"2023","unstructured":"Khawar, M. M. Sr. et al. The gut\u2013brain axis in autoimmune diseases: emerging insights and therapeutic implications. Cureus 15, e48655 (2023).","journal-title":"Cureus"},{"key":"2735_CR45","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/nrgastro.2016.107","volume":"13","author":"M Rao","year":"2016","unstructured":"Rao, M. & Gershon, M. D. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 517\u2013528 (2016).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2735_CR46","doi-asserted-by":"publisher","first-page":"39226","DOI":"10.31083\/AP39226","volume":"26","author":"Y-A Xie","year":"2025","unstructured":"Xie, Y.-A., Kong, J.-D., Li, S. & Wei, D.-F. What is the impact of dopamine D2 receptor in the brain\u2013gut axis? A narrative review of the mechanism based on gut microbiota in modulating emotion and behavior. Alpha Psychiatry 26, 39226 (2025).","journal-title":"Alpha Psychiatry"},{"key":"2735_CR47","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.18154","volume":"28","author":"X Lu","year":"2024","unstructured":"Lu, X. et al. Research progress on the roles of dopamine and dopamine receptors in digestive system diseases. J. Cell. Mol. Med. 28, e18154 (2024).","journal-title":"J. Cell. Mol. Med."},{"key":"2735_CR48","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41385-021-00443-1","volume":"15","author":"H Wang","year":"2022","unstructured":"Wang, H., Foong, J. P. P., Harris, N. L. & Bornstein, J. C. Enteric neuroimmune interactions coordinate intestinal responses in health and disease. Mucosal Immunol. 15, 27\u201339 (2022).","journal-title":"Mucosal Immunol."},{"key":"2735_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01738-y","volume":"9","author":"L Cui","year":"2024","unstructured":"Cui, L. et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Sig. Transduct. Target. Ther. 9, 30 (2024).","journal-title":"Sig. Transduct. Target. Ther."},{"key":"2735_CR50","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/s41380-024-02771-7","volume":"30","author":"DJ Woodward","year":"2025","unstructured":"Woodward, D. J. et al. Leveraging pleiotropy for the improved treatment of psychiatric disorders. Mol. Psychiatry 30, 705\u2013721 (2025).","journal-title":"Mol. Psychiatry"},{"key":"2735_CR51","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1981","volume":"11","author":"C Van der Feltz-Cornelis","year":"2020","unstructured":"Van der Feltz-Cornelis, C. et al. Treatment for comorbid depressive disorder or subthreshold depression in diabetes mellitus: systematic review and meta-analysis. Brain Behav. 11, e01981 (2020).","journal-title":"Brain Behav."},{"key":"2735_CR52","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1111\/acps.13016","volume":"139","author":"O K\u00f6hler-Forsberg","year":"2019","unstructured":"K\u00f6hler-Forsberg, O. et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr. Scand. 139, 404\u2013419 (2019).","journal-title":"Acta Psychiatr. Scand."},{"key":"2735_CR53","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1176\/appi.ajp.2016.15040463","volume":"173","author":"O K\u00f6hler","year":"2016","unstructured":"K\u00f6hler, O. et al. The effect of concomitant treatment with SSRIs and statins: a population-based study. Am. J. Psychiatry 173, 807\u2013815 (2016).","journal-title":"Am. J. Psychiatry"},{"key":"2735_CR54","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.jpsychores.2014.12.009","volume":"78","author":"JF Henrich","year":"2015","unstructured":"Henrich, J. F. et al. Identifying effective techniques within psychological treatments for irritable bowel syndrome: a meta-analysis. J. Psychosom. Res. 78, 205\u2013222 (2015).","journal-title":"J. Psychosom. Res."},{"key":"2735_CR55","doi-asserted-by":"publisher","DOI":"10.1007\/s11894-018-0664-3","volume":"20","author":"H T\u00f6rnblom","year":"2018","unstructured":"T\u00f6rnblom, H. & Drossman, D. A. Psychotropics, antidepressants, and visceral analgesics in functional gastrointestinal disorders. Curr. Gastroenterol. Rep. 20, 58 (2018).","journal-title":"Curr. Gastroenterol. Rep."},{"key":"2735_CR56","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.21r14328","volume":"83","author":"AM Arnaud","year":"2022","unstructured":"Arnaud, A. M. et al. Impact of major depressive disorder on comorbidities: a systematic literature review. J. Clin. Psychiatry 83, 43390 (2022).","journal-title":"J. Clin. Psychiatry"},{"key":"2735_CR57","doi-asserted-by":"publisher","first-page":"2254","DOI":"10.1038\/s41380-023-01957-9","volume":"28","author":"J Flint","year":"2023","unstructured":"Flint, J. The genetic basis of major depressive disorder. Mol. Psychiatry 28, 2254\u20132265 (2023).","journal-title":"Mol. Psychiatry"},{"key":"2735_CR58","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25115933","volume":"25","author":"E Layunta","year":"2024","unstructured":"Layunta, E., Mesonero, J. E. & Latorre, E. Guardians at the gate: immune system in gastrointestinal diseases. Int. J. Mol. Sci. 25, 5933 (2024).","journal-title":"Int. J. Mol. Sci."},{"key":"2735_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38389-6","volume":"14","author":"P Demela","year":"2023","unstructured":"Demela, P., Pirastu, N. & Soskic, B. Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways. Nat. Commun. 14, 2743 (2023).","journal-title":"Nat. Commun."},{"key":"2735_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-025-03470-9","volume":"15","author":"S Breunig","year":"2025","unstructured":"Breunig, S. et al. Examining the genetic links between clusters of immune-mediated diseases and psychiatric disorders. Transl. Psychiatry 15, 252 (2025).","journal-title":"Transl. Psychiatry"},{"key":"2735_CR61","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","volume":"47","author":"BK Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291\u2013295 (2015).","journal-title":"Nat. Genet."},{"key":"2735_CR62","unstructured":"Revelle, W. Psych: procedures for psychological, psychometric, and personality research. https:\/\/cran.r-project.org\/web\/packages\/psych\/index.html (2026)."},{"key":"2735_CR63","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5","volume":"8","author":"K Watanabe","year":"2017","unstructured":"Watanabe, K., Taskesen, E., Van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).","journal-title":"Nat. Commun."},{"key":"2735_CR64","doi-asserted-by":"publisher","first-page":"D1353","DOI":"10.1093\/nar\/gkac1046","volume":"51","author":"D Ochoa","year":"2023","unstructured":"Ochoa, D. et al. The next-generation Open Targets Platform: reimagined, redesigned, rebuilt. Nucleic Acids Res. 51, D1353\u2013D1359 (2023).","journal-title":"Nucleic Acids Res."},{"key":"2735_CR65","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","volume":"26","author":"AR Quinlan","year":"2010","unstructured":"Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841\u2013842 (2010).","journal-title":"Bioinformatics"},{"key":"2735_CR66","doi-asserted-by":"publisher","first-page":"D1265","DOI":"10.1093\/nar\/gkad976","volume":"52","author":"C Knox","year":"2024","unstructured":"Knox, C. et al. DrugBank 6.0: the DrugBank knowledgebase for 2024. Nucleic Acids Res. 52, D1265\u2013D1275 (2024).","journal-title":"Nucleic Acids Res."},{"key":"2735_CR67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219","volume":"11","author":"CA De Leeuw","year":"2015","unstructured":"De Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015).","journal-title":"PLoS Comput. Biol."},{"key":"2735_CR68","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","volume":"45","author":"J Lonsdale","year":"2013","unstructured":"Lonsdale, J. et al. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580\u2013585 (2013).","journal-title":"Nat. Genet."},{"key":"2735_CR69","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/s41588-020-0610-9","volume":"52","author":"J Bryois","year":"2020","unstructured":"Bryois, J. et al. Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson\u2019s disease. Nat. Genet. 52, 482\u2013493 (2020).","journal-title":"Nat. Genet."},{"key":"2735_CR70","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1038\/s41586-025-08757-x","volume":"641","author":"L Song","year":"2025","unstructured":"Song, L., Chen, W., Hou, J., Guo, M. & Yang, J. Spatially resolved mapping of cells associated with human complex traits. Nature 641, 932\u2013941 (2025).","journal-title":"Nature"},{"key":"2735_CR71","unstructured":"NanoString Technologies. CosMx SMI human frontal cortex FFPE dataset. Bruker Spatial Biology https:\/\/brukerspatialbiology.com\/products\/cosmx-spatial-molecular-imager\/ffpe-dataset\/human-frontal-cortex-ffpe-dataset\/ (2021)."},{"key":"2735_CR72","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1038\/s41587-022-01483-z","volume":"40","author":"S He","year":"2022","unstructured":"He, S. et al. High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging. Nat. Biotechnol. 40, 1794\u20131806 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2735_CR73","doi-asserted-by":"publisher","unstructured":"Woodward, D. et al. Dissecting pleiotropy between major depressive disorder and physical disease comorbidities [computer software]. Zenodo https:\/\/doi.org\/10.5281\/zenodo.21711189 (2026).","DOI":"10.5281\/zenodo.21711189"}],"container-title":["Nature Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02735-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02735-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02735-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:03:15Z","timestamp":1788890595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41588-026-02735-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":73,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["2735"],"URL":"https:\/\/doi.org\/10.1038\/s41588-026-02735-3","relation":{},"ISSN":["1061-4036","1546-1718"],"issn-type":[{"value":"1061-4036","type":"print"},{"value":"1546-1718","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"assertion":[{"value":"7 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}