{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:27:04Z","timestamp":1793035624872,"version":"4.5.0"},"reference-count":139,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Legal and General"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Aging"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Delirium is an acute change in cognition, common in hospitalized older adults, and associated with high healthcare and human cost; however, delirium\u2019s genetic and proteomic background remains poorly understood. Here we conducted a genetic meta-analysis on delirium using multi-ancestry data from the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative cohorts (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009\n                    <jats:italic>=<\/jats:italic>\n                    \u20091,059,130; 11,931 cases), yielding the\n                    <jats:italic>Apolipoprotein E<\/jats:italic>\n                    (\n                    <jats:italic>APOE<\/jats:italic>\n                    ) gene as a strong delirium risk factor independently of dementia. A multi-trait analysis of delirium with Alzheimer disease identified five delirium genetic risk loci. Plasma proteins associated with up to 16-year incident delirium in UK Biobank (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009\n                    <jats:italic>=<\/jats:italic>\n                    \u200932,652; 541 cases) revealed protein biomarkers implicating brain vulnerability, inflammation and immune response processes. Incorporating proteomic and genetic evidence via Mendelian randomization, colocalization and druggability analyses, we indicate potentially useful drug target proteins for delirium. Combining proteins,\n                    <jats:italic>APOE-<\/jats:italic>\n                    \u03b54 status and demographics significantly improved incident delirium prediction compared to demographics alone. Our results provide insight into delirium\u2019s etiology and may guide further research on clinically relevant biomarkers.\n                  <\/jats:p>","DOI":"10.1038\/s43587-025-01018-6","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:02:34Z","timestamp":1763978554000},"page":"235-251","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Dissecting the genetic and proteomic risk factors for delirium"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2579-0421","authenticated-orcid":false,"given":"Vasilis","family":"Raptis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngjune","family":"Bhak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2111-4168","authenticated-orcid":false,"given":"Timothy I.","family":"Cannings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair M. J.","family":"MacLullich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4884-4475","authenticated-orcid":false,"given":"Albert","family":"Tenesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"1018_CR1","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.mpmed.2020.10.002","volume":"49","author":"A Anand","year":"2021","unstructured":"Anand, A. & MacLullich, A. M. J. Delirium in older adults. Medicine 49, 26\u201331 (2021).","journal-title":"Medicine"},{"key":"1018_CR2","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013).","DOI":"10.1176\/appi.books.9780890425596"},{"key":"1018_CR3","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41572-020-00223-4","volume":"6","author":"JE Wilson","year":"2020","unstructured":"Wilson, J. E. et al. Delirium. Nat. Rev. Dis. Prim. 6, 90 (2020).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"1018_CR4","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/S0140-6736(13)60688-1","volume":"383","author":"SK Inouye","year":"2014","unstructured":"Inouye, S. K., Westendorp, R. G. & Saczynski, J. S. Delirium in elderly people. Lancet 383, 911\u2013922 (2014).","journal-title":"Lancet"},{"key":"1018_CR5","doi-asserted-by":"publisher","unstructured":"Gordon, E. H., Ward, D. D., Xiong, H., Berkovsky, S. & Hubbard, R. E. Delirium and incident dementia in hospital patients in New South Wales, Australia: retrospective cohort study. BMJ https:\/\/doi.org\/10.1136\/bmj-2023-077634 (2024).","DOI":"10.1136\/bmj-2023-077634"},{"key":"1018_CR6","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/s41582-022-00698-7","volume":"18","author":"TG Fong","year":"2022","unstructured":"Fong, T. G. & Inouye, S. K. The inter-relationship between delirium and dementia: the importance of delirium prevention. Nat. Rev. Neurol. 18, 579\u2013596 (2022).","journal-title":"Nat. Rev. Neurol."},{"key":"1018_CR7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163472","volume":"133","author":"LO Watne","year":"2023","unstructured":"Watne, L. O. et al. Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients. J. Clin. Invest. 133, e163472 (2023).","journal-title":"J. Clin. Invest."},{"key":"1018_CR8","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae319","volume":"6","author":"A Tsui","year":"2024","unstructured":"Tsui, A. et al. Persistent delirium is associated with cerebrospinal fluid markers of neuronal injury. Brain Commun. 6, fcae319 (2024).","journal-title":"Brain Commun."},{"key":"1018_CR9","doi-asserted-by":"publisher","first-page":"e399","DOI":"10.1016\/S2666-7568(23)00098-3","volume":"4","author":"M Krogseth","year":"2023","unstructured":"Krogseth, M. et al. Delirium, neurofilament light chain, and progressive cognitive impairment: analysis of a prospective Norwegian population-based cohort. Lancet Healthy Longev. 4, e399\u2013e408 (2023).","journal-title":"Lancet Healthy Longev."},{"key":"1018_CR10","doi-asserted-by":"publisher","unstructured":"Heneka, M. T. et al. Neuroinflammation in Alzheimer disease. Nat. Rev. Immunol. https:\/\/doi.org\/10.1038\/s41577-024-01104-7 (2024).","DOI":"10.1038\/s41577-024-01104-7"},{"key":"1018_CR11","doi-asserted-by":"publisher","unstructured":"Leslie, D. L. & Inouye, S. K. The importance of delirium: economic and societal costs. J. Am. Geriat. Soc. https:\/\/doi.org\/10.1111\/j.1532-5415.2011.03671.x (2011).","DOI":"10.1111\/j.1532-5415.2011.03671.x"},{"key":"1018_CR12","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1007\/s00406-021-01255-x","volume":"271","author":"E Sepulveda","year":"2021","unstructured":"Sepulveda, E. et al. The complex interaction of genetics and delirium: a systematic review and meta-analysis. Eur. Arch. Psychiatry Clin. Neurosci. 271, 929\u2013939 (2021).","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"1018_CR13","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1002\/gps.4496","volume":"32","author":"L Massimo","year":"2017","unstructured":"Massimo, L. et al. Genetic and environmental factors associated with delirium severity in older adults with dementia. Int. J. Geriat. Psychiatry 32, 574\u2013581 (2017).","journal-title":"Int. J. Geriat. Psychiatry"},{"key":"1018_CR14","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1002\/ajmg.b.30943","volume":"153B","author":"BC Van Munster","year":"2010","unstructured":"Van Munster, B. C. et al. Genetic polymorphisms in the DRD2, DRD3, and SLC6A3 gene in elderly patients with delirium. Am. J. Med Genet. B 153B, 38\u201345 (2010).","journal-title":"Am. J. Med Genet. B"},{"key":"1018_CR15","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1097\/01.CCM.0000251925.18961.CA","volume":"35","author":"WE Ely","year":"2007","unstructured":"Ely, W. E. et al. Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit. Care Med. 35, 112\u2013117 (2007).","journal-title":"Crit. Care Med."},{"key":"1018_CR16","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1111\/j.1440-1819.2005.01355.x","volume":"59","author":"J Kim","year":"2005","unstructured":"Kim, J. et al. Antipsychotics and dopamine transporter gene polymorphisms in delirium patients. Psychiatry Clin. Neurosci. 59, 183\u2013188 (2005).","journal-title":"Psychiatry Clin. Neurosci."},{"key":"1018_CR17","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1097\/YPG.0b013e3280c8efd4","volume":"17","author":"BC Van Munster","year":"2007","unstructured":"Van Munster, B. C., Korevaar, J. C., De Rooij, S. E., Levi, M. & Zwinderman, A. H. The association between delirium and the apolipoprotein E \u03b54 allele in the elderly. Psychiatr. Genet. 17, 261\u2013266 (2007).","journal-title":"Psychiatr. Genet."},{"key":"1018_CR18","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1089\/rej.2011.1155","volume":"14","author":"BC Van Munster","year":"2011","unstructured":"Van Munster, B. C., Zwinderman, A. H. & De Rooij, S. E. Genetic variations in the interleukin-6 and interleukin-8 genes and the interleukin-6 receptor gene in delirium. Rejuvenation Res. 14, 425\u2013428 (2011).","journal-title":"Rejuvenation Res."},{"key":"1018_CR19","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1097\/01.anes.0000278905.07899.df","volume":"107","author":"JM Leung","year":"2007","unstructured":"Leung, J. M. et al. Apolipoprotein E e4 allele increases the risk of early postoperative delirium in older patients undergoing noncardiac surgery. Anesthesiology 107, 406\u2013411 (2007).","journal-title":"Anesthesiology"},{"key":"1018_CR20","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1093\/ageing\/afx042","volume":"46","author":"EL Cunningham","year":"2017","unstructured":"Cunningham, E. L. et al. Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population. Age Ageing 46, 779\u2013786 (2017).","journal-title":"Age Ageing"},{"key":"1018_CR21","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1097\/JGP.0b013e3181ab8c84","volume":"17","author":"BC Van Munster","year":"2009","unstructured":"Van Munster, B. C., Korevaar, J. C., Zwinderman, A. H., Leeflang, M. M. & De Rooij, S. E. J. A. The association between delirium and the apolipoprotein e epsilon 4 allele: new study results and a meta-analysis. Am. J. Geriatr. Psychiatry 17, 856\u2013862 (2009).","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"1018_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-04416-z","volume":"12","author":"M Terrelonge","year":"2022","unstructured":"Terrelonge, M. et al. KIBRA, MTNR1B, and FKBP5 genotypes are associated with decreased odds of incident delirium in elderly post-surgical patients. Sci. Rep. 12, 556 (2022).","journal-title":"Sci. Rep."},{"key":"1018_CR23","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1097\/YPG.0000000000000122","volume":"26","author":"D Adamis","year":"2016","unstructured":"Adamis, D., Meagher, D., Williams, J., Mulligan, O. & McCarthy, G. A systematic review and meta-analysis of the association between the apolipoprotein E genotype and delirium. Psychiatr. Genet. 26, 53\u201359 (2016).","journal-title":"Psychiatr. Genet."},{"key":"1018_CR24","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.ajhg.2017.06.005","volume":"101","author":"PM Visscher","year":"2017","unstructured":"Visscher, P. M. et al. 10 years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5\u201322 (2017).","journal-title":"Am. J. Hum. Genet."},{"key":"1018_CR25","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/S1474-4422(19)30287-X","volume":"19","author":"C Blauwendraat","year":"2020","unstructured":"Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson\u2019s disease. Lancet Neurol. 19, 170\u2013178 (2020).","journal-title":"Lancet Neurol."},{"key":"1018_CR26","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-018-0874-y","volume":"18","author":"T Orme","year":"2018","unstructured":"Orme, T., Guerreiro, R. & Bras, J. The genetics of dementia with Lewy bodies: current understanding and future directions. Curr. Neurol. Neurosci. Rep. 18, 67 (2018).","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"1018_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104511","volume":"90","author":"SJ Andrews","year":"2023","unstructured":"Andrews, S. J. et al. The complex genetic architecture of Alzheimer\u2019s disease: novel insights and future directions. eBioMedicine 90, 104511 (2023).","journal-title":"eBioMedicine"},{"key":"1018_CR28","doi-asserted-by":"publisher","first-page":"160.e9","DOI":"10.1016\/j.neurobiolaging.2018.03.008","volume":"68","author":"TH McCoy","year":"2018","unstructured":"McCoy, T. H., Hart, K., Pellegrini, A. & Perlis, R. H. Genome-wide association identifies a novel locus for delirium risk. Neurobiol. Aging 68, 160.e9\u2013160.e14 (2018).","journal-title":"Neurobiol. Aging"},{"key":"1018_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-021-01071-1","volume":"14","author":"M Heinrich","year":"2021","unstructured":"Heinrich, M. et al. Association between genetic variants of the cholinergic system and postoperative delirium and cognitive dysfunction in elderly patients. BMC Med Genomics 14, 248 (2021).","journal-title":"BMC Med Genomics"},{"key":"1018_CR30","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12872-019-1002-x","volume":"19","author":"S Westphal","year":"2019","unstructured":"Westphal, S. et al. Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery \u2013 a sub-analysis of the RIPHeart-Study. BMC Cardiovasc. Disord. 19, 26 (2019).","journal-title":"BMC Cardiovasc. Disord."},{"key":"1018_CR31","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1213\/ANE.0000000000006246","volume":"136","author":"K Wiredu","year":"2023","unstructured":"Wiredu, K., Aduse-Poku, E., Shaefi, S. & Gerber, S. A. Proteomics for the discovery of clinical delirium biomarkers: a systematic review of major studies. Anesthesia Analgesia 136, 422\u2013432 (2023).","journal-title":"Anesthesia Analgesia"},{"key":"1018_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-82992-6","volume":"15","author":"MP Mosharaf","year":"2025","unstructured":"Mosharaf, M. P., Alam, K., Gow, J. & Mahumud, R. A. Cytokines and inflammatory biomarkers and their association with post-operative delirium: a meta-analysis and systematic review. Sci. Rep. 15, 7830 (2025).","journal-title":"Sci. Rep."},{"key":"1018_CR33","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203\u2013209 (2018).","journal-title":"Nature"},{"key":"1018_CR34","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/s41588-017-0009-4","volume":"50","author":"P Turley","year":"2018","unstructured":"Turley, P. et al. Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat. Genet. 50, 229\u2013237 (2018).","journal-title":"Nat. Genet."},{"key":"1018_CR35","doi-asserted-by":"publisher","first-page":"102954","DOI":"10.1016\/j.ebiom.2020.102954","volume":"59","author":"AL Lumsden","year":"2020","unstructured":"Lumsden, A. L., Mulugeta, A., Zhou, A. & Hypp\u00f6nen, E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. eBioMedicine 59, 102954 (2020).","journal-title":"eBioMedicine"},{"key":"1018_CR36","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1097\/EDE.0000000000001064","volume":"30","author":"LH Smith","year":"2019","unstructured":"Smith, L. H. & VanderWeele, T. J. Mediational E-values: approximate sensitivity analysis for unmeasured mediator-outcome confounding. Epidemiology 30, 835\u2013837 (2019).","journal-title":"Epidemiology"},{"key":"1018_CR37","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","volume":"58","author":"R Tibshirani","year":"1996","unstructured":"Tibshirani, R. Regression shrinkage and selection via the lasso. J. R. Stat. Soc. B 58, 267\u2013288 (1996).","journal-title":"J. R. Stat. Soc. B"},{"key":"1018_CR38","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1111\/j.1467-9868.2010.00740.x","volume":"72","author":"N Meinshausen","year":"2010","unstructured":"Meinshausen, N. & B\u00fchlmann, P. Stability selection. J. R. Stat. Soc. B 72, 417\u2013473 (2010).","journal-title":"J. R. Stat. Soc. B"},{"key":"1018_CR39","doi-asserted-by":"publisher","first-page":"e1004383","DOI":"10.1371\/journal.pgen.1004383","volume":"10","author":"C Giambartolomei","year":"2014","unstructured":"Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).","journal-title":"PLoS Genet."},{"key":"1018_CR40","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.ajhg.2022.04.001","volume":"109","author":"V Zuber","year":"2022","unstructured":"Zuber, V. et al. Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches. Am. J. Hum. Genet. 109, 767\u2013782 (2022).","journal-title":"Am. J. Hum. Genet."},{"key":"1018_CR41","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag1166","volume":"9","author":"C Finan","year":"2017","unstructured":"Finan, C. et al. The druggable genome and support for target identification and validation in drug development. Sci. Transl. Med. 9, eaag1166 (2017).","journal-title":"Sci. Transl. Med."},{"key":"1018_CR42","doi-asserted-by":"publisher","unstructured":"Huang, K. et al. Small-cohort GWAS discovery with AI over massive functional genomics knowledge graph. Preprint at medRxiv https:\/\/doi.org\/10.1101\/2024.12.03.24318375 (2024).","DOI":"10.1101\/2024.12.03.24318375"},{"key":"1018_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-022-00574-4","volume":"17","author":"A-C Raulin","year":"2022","unstructured":"Raulin, A.-C. et al. ApoE in Alzheimer\u2019s disease: pathophysiology and therapeutic strategies. Mol. Neurodegeneration 17, 72 (2022).","journal-title":"Mol. Neurodegeneration"},{"key":"1018_CR44","doi-asserted-by":"publisher","unstructured":"Bowman, K. et al. Vitamin D levels and risk of delirium: a Mendelian randomization study in the UK Biobank. Neurology https:\/\/doi.org\/10.1212\/wnl.0000000000007136 (2019).","DOI":"10.1212\/wnl.0000000000007136"},{"key":"1018_CR45","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1038\/s41418-022-01027-7","volume":"29","author":"W Xie","year":"2022","unstructured":"Xie, W. et al. CEND1 deficiency induces mitochondrial dysfunction and cognitive impairment in Alzheimer\u2019s disease. Cell Death Differ. 29, 2417\u20132428 (2022).","journal-title":"Cell Death Differ."},{"key":"1018_CR46","doi-asserted-by":"publisher","first-page":"e39","DOI":"10.1038\/emm.2013.76","volume":"45","author":"A Manavalan","year":"2013","unstructured":"Manavalan, A. et al. Brain site-specific proteome changes in aging-related dementia. Exp. Mol. Med 45, e39 (2013).","journal-title":"Exp. Mol. Med"},{"key":"1018_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-02776-4","volume":"11","author":"E Schmukler","year":"2020","unstructured":"Schmukler, E. et al. Altered mitochondrial dynamics and function in APOE4-expressing astrocytes. Cell Death Dis. 11, 578 (2020).","journal-title":"Cell Death Dis."},{"key":"1018_CR48","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","volume":"278","author":"LA Farrer","year":"1997","unstructured":"Farrer, L. A. Effects of age, sex, and ethnicity on the association between apolipoprotein e genotype and Alzheimer disease: a meta-analysis. JAMA 278, 1349\u20131356 (1997).","journal-title":"JAMA"},{"key":"1018_CR49","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1001\/jamaneurol.2023.3599","volume":"80","author":"ME Belloy","year":"2023","unstructured":"Belloy, M. E. et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 80, 1284\u20131294 (2023).","journal-title":"JAMA Neurol."},{"key":"1018_CR50","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1002\/alz.12287","volume":"17","author":"AJ Griswold","year":"2021","unstructured":"Griswold, A. J. et al. Increased APOE \u03b54 expression is associated with the difference in Alzheimer\u2019s disease risk from diverse ancestral backgrounds. Alzheimer\u2019s Dement. 17, 1179\u20131188 (2021).","journal-title":"Alzheimer\u2019s Dement."},{"key":"1018_CR51","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.neurobiolaging.2020.04.024","volume":"93","author":"E Bellou","year":"2020","unstructured":"Bellou, E. et al. Age-dependent effect of APOE and polygenic component on Alzheimer\u2019s disease. Neurobiol. Aging 93, 69\u201377 (2020).","journal-title":"Neurobiol. Aging"},{"key":"1018_CR52","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1002\/acn3.333","volume":"3","author":"LW Bonham","year":"2016","unstructured":"Bonham, L. W. et al. Age-dependent effects of APOE \u03b54 in preclinical Alzheimer\u2019s disease. Ann. Clin. Transl. Neurol. 3, 668\u2013677 (2016).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"1018_CR53","doi-asserted-by":"publisher","unstructured":"Steen, J., Loeys, T., Moerkerke, B. & Vansteelandt, S. Medflex: an R package for flexible mediation analysis using natural effect models. J. Stat. Soft. https:\/\/doi.org\/10.18637\/jss.v076.i11 (2017).","DOI":"10.18637\/jss.v076.i11"},{"key":"1018_CR54","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1136\/jnnp-2022-328903","volume":"93","author":"SP Leighton","year":"2022","unstructured":"Leighton, S. P. et al. Delirium and the risk of developing dementia: a cohort study of 12 949 patients. J. Neurol. Neurosurg. Psychiatry 93, 822\u2013827 (2022).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"1018_CR55","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/S0140-6736(24)01296-0","volume":"404","author":"G Livingston","year":"2024","unstructured":"Livingston, G. et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet 404, 572\u2013628 (2024).","journal-title":"Lancet"},{"key":"1018_CR56","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.mam.2008.08.001","volume":"29","author":"D Edwards","year":"2008","unstructured":"Edwards, D., Handsley, M. & Pennington, C. The ADAM metalloproteinases. Mol. Asp. Med. 29, 258\u2013289 (2008).","journal-title":"Mol. Asp. Med."},{"key":"1018_CR57","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/s41577-018-0068-5","volume":"18","author":"BN Lambrecht","year":"2018","unstructured":"Lambrecht, B. N., Vanderkerken, M. & Hammad, H. The emerging role of ADAM metalloproteinases in immunity. Nat. Rev. Immunol. 18, 745\u2013758 (2018).","journal-title":"Nat. Rev. Immunol."},{"key":"1018_CR58","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","volume":"54","author":"C Bellenguez","year":"2022","unstructured":"Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias. Nat. Genet. 54, 412\u2013436 (2022).","journal-title":"Nat. Genet."},{"key":"1018_CR59","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1038\/s41590-019-0417-y","volume":"20","author":"I Mattiola","year":"2019","unstructured":"Mattiola, I. et al. The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell\u2013mediated resistance to metastasis. Nat. Immunol. 20, 1012\u20131022 (2019).","journal-title":"Nat. Immunol."},{"key":"1018_CR60","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1007\/s10142-023-01270-2","volume":"23","author":"J Chen","year":"2023","unstructured":"Chen, J., Zhao, X., Huang, C. & Lin, J. Novel insights into molecular signatures and pathogenic cell populations shared by systemic lupus erythematosus and vascular dementia. Funct. Integr. Genomics 23, 337 (2023).","journal-title":"Funct. Integr. Genomics"},{"key":"1018_CR61","doi-asserted-by":"publisher","unstructured":"Saha, O. et al. The Alzheimer\u2019s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons. Mol. Psychiatry https:\/\/doi.org\/10.1038\/s41380-024-02502-y (2024).","DOI":"10.1038\/s41380-024-02502-y"},{"key":"1018_CR62","doi-asserted-by":"publisher","first-page":"164","DOI":"10.3389\/fnins.2019.00164","volume":"13","author":"EM Foster","year":"2019","unstructured":"Foster, E. M., Dangla-Valls, A., Lovestone, S., Ribe, E. M. & Buckley, N. J. Clusterin in Alzheimer\u2019s disease: mechanisms, genetics, and lessons from other pathologies. Front. Neurosci. 13, 164 (2019).","journal-title":"Front. Neurosci."},{"key":"1018_CR63","doi-asserted-by":"publisher","first-page":"e477","DOI":"10.1038\/tp.2014.114","volume":"4","author":"A Poljak","year":"2014","unstructured":"Poljak, A. et al. Quantitative proteomics of delirium cerebrospinal fluid. Transl. Psychiatry 4, e477 (2014).","journal-title":"Transl. Psychiatry"},{"key":"1018_CR64","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1007\/s12035-014-8723-8","volume":"51","author":"X-C Zhu","year":"2015","unstructured":"Zhu, X.-C. et al. CR1 in Alzheimer\u2019s disease. Mol. Neurobiol. 51, 753\u2013765 (2015).","journal-title":"Mol. Neurobiol."},{"key":"1018_CR65","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.jalz.2016.03.015","volume":"12","author":"A Roses","year":"2016","unstructured":"Roses, A. et al. Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer\u2019s disease. Alzheimer\u2019s Dement. 12, 687\u2013694 (2016).","journal-title":"Alzheimer\u2019s Dement."},{"key":"1018_CR66","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1007\/s40520-020-01661-6","volume":"33","author":"Z Zhu","year":"2021","unstructured":"Zhu, Z. et al. TOMM40 and APOE variants synergistically increase the risk of Alzheimer\u2019s disease in a Chinese population. Aging Clin. Exp. Res. 33, 1667\u20131675 (2021).","journal-title":"Aging Clin. Exp. Res."},{"key":"1018_CR67","doi-asserted-by":"publisher","first-page":"e6044","DOI":"10.1002\/gps.6044","volume":"39","author":"TG Fong","year":"2024","unstructured":"Fong, T. G. et al. Biomarkers of neurodegeneration and neural injury as potential predictors for delirium. Int. J. Geriat. Psychiatry 39, e6044 (2024).","journal-title":"Int. J. Geriat. Psychiatry"},{"key":"1018_CR68","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1002\/ana.25889","volume":"88","author":"TG Fong","year":"2020","unstructured":"Fong, T. G. et al. Association of plasma neurofilament light with postoperative delirium. Ann. Neurol. 88, 984\u2013994 (2020).","journal-title":"Ann. Neurol."},{"key":"1018_CR69","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1089\/rej.2011.1185","volume":"14","author":"BC Van Munster","year":"2011","unstructured":"Van Munster, B. C. et al. Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation Res. 14, 615\u2013622 (2011).","journal-title":"Rejuvenation Res."},{"key":"1018_CR70","doi-asserted-by":"publisher","first-page":"7316","DOI":"10.1080\/21655979.2022.2048775","volume":"13","author":"Y Miao","year":"2022","unstructured":"Miao, Y., Wang, M., Cai, X., Zhu, Q. & Mao, L. Leucine rich \u03b1-2-glycoprotein 1 (Lrg1) silencing protects against sepsis-mediated brain injury by inhibiting transforming growth factor \u03b21 (TGF\u03b21)\/SMAD signaling pathway. Bioengineered 13, 7316\u20137327 (2022).","journal-title":"Bioengineered"},{"key":"1018_CR71","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-34447-7","volume":"13","author":"RL Oren","year":"2023","unstructured":"Oren, R. L. et al. Age-dependent differences and similarities in the plasma proteomic signature of postoperative delirium. Sci. Rep. 13, 7431 (2023).","journal-title":"Sci. Rep."},{"key":"1018_CR72","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1159\/000533789","volume":"69","author":"SM Vasunilashorn","year":"2023","unstructured":"Vasunilashorn, S. M., Dillon, S. T., Marcantonio, E. R. & Libermann, T. A. Application of multiple omics to understand postoperative delirium pathophysiology in humans. Gerontology 69, 1369\u20131384 (2023).","journal-title":"Gerontology"},{"key":"1018_CR73","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.bbi.2020.06.027","volume":"89","author":"AM Peters Van Ton","year":"2020","unstructured":"Peters Van Ton, A. M., Verbeek, M. M., Alkema, W., Pickkers, P. & Abdo, W. F. Downregulation of synapse-associated protein expression and loss of homeostatic microglial control in cerebrospinal fluid of infectious patients with delirium and patients with Alzheimer\u2019s disease. Brain Behav. Immun. 89, 656\u2013667 (2020).","journal-title":"Brain Behav. Immun."},{"key":"1018_CR74","doi-asserted-by":"publisher","unstructured":"Juji\u0107, A. et al. Low levels of selenoprotein P are associated with cognitive impairment in patients hospitalized for heart failure. J. Cardiac Fail. https:\/\/doi.org\/10.1016\/j.cardfail.2024.01.010 (2024).","DOI":"10.1016\/j.cardfail.2024.01.010"},{"key":"1018_CR75","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.semcdb.2014.01.005","volume":"28","author":"C Berasain","year":"2014","unstructured":"Berasain, C. & Avila, M. A. Amphiregulin. Semin. Cell Dev. Biol. 28, 31\u201341 (2014).","journal-title":"Semin. Cell Dev. Biol."},{"key":"1018_CR76","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110800","volume":"124","author":"Y Hong","year":"2023","unstructured":"Hong, Y. et al. Sepsis-associated encephalopathy: from pathophysiology to clinical management. Int. Immunopharmacol. 124, 110800 (2023).","journal-title":"Int. Immunopharmacol."},{"key":"1018_CR77","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.immuni.2015.01.020","volume":"42","author":"DMW Zaiss","year":"2015","unstructured":"Zaiss, D. M. W., Gause, W. C., Osborne, L. C. & Artis, D. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42, 216\u2013226 (2015).","journal-title":"Immunity"},{"key":"1018_CR78","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1038\/s41591-023-02452-y","volume":"29","author":"R Hassan","year":"2023","unstructured":"Hassan, R. et al. Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1\/2 trial interim results. Nat. Med. 29, 2099\u20132109 (2023).","journal-title":"Nat. Med."},{"key":"1018_CR79","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrclinonc.2014.147","volume":"12","author":"PG Lawlor","year":"2015","unstructured":"Lawlor, P. G. & Bush, S. H. Delirium in patients with cancer: assessment, impact, mechanisms and management. Nat. Rev. Clin. Oncol. 12, 77\u201392 (2015).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"1018_CR80","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-020-02584-2","volume":"20","author":"I Amgarth-Duff","year":"2020","unstructured":"Amgarth-Duff, I., Hosie, A., Caplan, G. & Agar, M. A systematic review of the overlap of fluid biomarkers in delirium and advanced cancer-related syndromes. BMC Psychiatry 20, 182 (2020).","journal-title":"BMC Psychiatry"},{"key":"1018_CR81","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1111\/nan.12529","volume":"45","author":"M Tzioras","year":"2019","unstructured":"Tzioras, M., Davies, C., Newman, A., Jackson, R. & Spires-Jones, T. Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer\u2019s disease. Neuropathol. Appl. Neurobiol. 45, 327\u2013346 (2019).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"1018_CR82","doi-asserted-by":"publisher","first-page":"8615","DOI":"10.1002\/alz.14302","volume":"20","author":"ET Reas","year":"2024","unstructured":"Reas, E. T. et al. APOE \u03b54-related blood\u2013brain barrier breakdown is associated with microstructural abnormalities. Alzheimer\u2019s Dement. 20, 8615\u20138624 (2024).","journal-title":"Alzheimer\u2019s Dement."},{"key":"1018_CR83","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/S1474-4422(20)30412-9","volume":"20","author":"A Serrano-Pozo","year":"2021","unstructured":"Serrano-Pozo, A., Das, S. & Hyman, B. T. APOE and Alzheimer\u2019s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 20, 68\u201380 (2021).","journal-title":"Lancet Neurol."},{"key":"1018_CR84","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.jns.2014.12.032","volume":"349","author":"S-T Yang","year":"2015","unstructured":"Yang, S.-T. et al. Accumulation of amyloid in cognitive impairment after mild traumatic brain injury. J. Neurol. Sci. 349, 99\u2013104 (2015).","journal-title":"J. Neurol. Sci."},{"key":"1018_CR85","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06301-2","volume":"9","author":"K Koizumi","year":"2018","unstructured":"Koizumi, K. et al. Apo\u03b54 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat. Commun. 9, 3816 (2018).","journal-title":"Nat. Commun."},{"key":"1018_CR86","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.3233\/JAD-191185","volume":"75","author":"KW VanDusen","year":"2020","unstructured":"VanDusen, K. W. et al. The MARBLE study protocol: modulating APOE signaling to reduce brain inflammation, delirium, and postoperative cognitive dysfunction. J. Alzheimer\u2019s Dis. 75, 1319\u20131328 (2020).","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"1018_CR87","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1038\/ng.3314","volume":"47","author":"MR Nelson","year":"2015","unstructured":"Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856\u2013860 (2015).","journal-title":"Nat. Genet."},{"key":"1018_CR88","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/s41586-024-07316-0","volume":"629","author":"EV Minikel","year":"2024","unstructured":"Minikel, E. V., Painter, J. L., Dong, C. C. & Nelson, M. R. Refining the impact of genetic evidence on clinical success. Nature 629, 624\u2013629 (2024).","journal-title":"Nature"},{"key":"1018_CR89","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/s41576-021-00387-z","volume":"22","author":"WR Reay","year":"2021","unstructured":"Reay, W. R. & Cairns, M. J. Advancing the use of genome-wide association studies for drug repurposing. Nat. Rev. Genet. 22, 658\u2013671 (2021).","journal-title":"Nat. Rev. Genet."},{"key":"1018_CR90","doi-asserted-by":"publisher","first-page":"33435","DOI":"10.1074\/jbc.M004543200","volume":"275","author":"DI Draganov","year":"2000","unstructured":"Draganov, D. I., Stetson, P. L., Watson, C. E., Billecke, S. S. & La Du, B. N. Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J. Biol. Chem. 275, 33435\u201333442 (2000).","journal-title":"J. Biol. Chem."},{"key":"1018_CR91","doi-asserted-by":"publisher","first-page":"e326","DOI":"10.1097\/MJT.0000000000001593","volume":"30","author":"Y-H Chang","year":"2023","unstructured":"Chang, Y.-H. et al. Statin use and delirium risk: an updated systematic review and meta-analysis. Am. J. Therapeutics 30, e326\u2013e335 (2023).","journal-title":"Am. J. Therapeutics"},{"key":"1018_CR92","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1080\/10408360802610878","volume":"46","author":"J Camps","year":"2009","unstructured":"Camps, J., Marsillach, J. & Joven, J. The paraoxonases: role in human diseases and methodological difficulties in measurement. Crit. Rev. Clin. Lab. Sci. 46, 83\u2013106 (2009).","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"1018_CR93","doi-asserted-by":"publisher","unstructured":"Grdic Rajkovic, M., Rumora, L. & Barisic, K. The paraoxonase 1, 2 and 3 in humans. Biochem. Med. https:\/\/doi.org\/10.11613\/BM.2011.020 (2011).","DOI":"10.11613\/BM.2011.020"},{"key":"1018_CR94","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7175","volume":"6","author":"U Schlomann","year":"2015","unstructured":"Schlomann, U. et al. ADAM8 as a drug target in pancreatic cancer. Nat. Commun. 6, 6175 (2015).","journal-title":"Nat. Commun."},{"key":"1018_CR95","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-13-47","volume":"13","author":"E Shubbar","year":"2013","unstructured":"Shubbar, E. et al. High levels of \u03b3-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer. BMC Cancer 13, 47 (2013).","journal-title":"BMC Cancer"},{"key":"1018_CR96","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-41649-6","volume":"13","author":"Q Li","year":"2023","unstructured":"Li, Q., Yang, Z., He, X. & Yang, X. Comprehensive analysis of PILR\u0391\u2019s association with the prognosis, tumor immune infiltration, and immunotherapy in pan-cancer. Sci. Rep. 13, 14334 (2023).","journal-title":"Sci. Rep."},{"key":"1018_CR97","doi-asserted-by":"publisher","unstructured":"Monroe, K. et al. PILRA regulates microglial neuroinflammation and lipid metabolism as a candidate therapeutic target for Alzheimer\u2019s disease. Preprint at Research Square https:\/\/doi.org\/10.21203\/rs.3.rs-3954863\/v1 (2024).","DOI":"10.21203\/rs.3.rs-3954863\/v1"},{"key":"1018_CR98","doi-asserted-by":"publisher","unstructured":"Ibitoye, T. et al. Delirium is under-reported in discharge summaries and in hospital administrative systems: a systematic review. Delirium https:\/\/doi.org\/10.56392\/001c.74541 (2023).","DOI":"10.56392\/001c.74541"},{"key":"1018_CR99","doi-asserted-by":"publisher","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","volume":"12","author":"C Sudlow","year":"2015","unstructured":"Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).","journal-title":"PLoS Med."},{"key":"1018_CR100","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/s41586-023-06957-x","volume":"627","author":"The All of Us Research Program Genomics Investigators et al.","year":"2024","unstructured":"The All of Us Research Program Genomics Investigators et al. Genomic data in the All of Us Research Program. Nature 627, 340\u2013346 (2024).","journal-title":"Nature"},{"key":"1018_CR101","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","volume":"613","author":"MI Kurki","year":"2023","unstructured":"Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508\u2013518 (2023).","journal-title":"Nature"},{"key":"1018_CR102","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2023.100257","volume":"3","author":"M Zawistowski","year":"2023","unstructured":"Zawistowski, M. et al. The Michigan Genomics Initiative: a biobank linking genotypes and electronic clinical records in Michigan medicine patients. Cell Genomics 3, 100257 (2023).","journal-title":"Cell Genomics"},{"key":"1018_CR103","unstructured":"World Health Organization. ICD-10: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (WHO, 2004)."},{"key":"1018_CR104","unstructured":"World Health Organization. International Classification of Diseases: Ninth Revision, Basic Tabulation List with Alphabetic Index (WHO, 1978)."},{"key":"1018_CR105","unstructured":"Stuart-Buttle, C. D., Read, J. D., Sanderson, H. F. & Sutton, Y. M. A language of health in action: Read Codes, classifications and groupings. Proc. AMIA Annu. Fall Symp. 1996, 75\u201379 (1996)."},{"key":"1018_CR106","doi-asserted-by":"publisher","first-page":"e63","DOI":"10.1016\/S2589-7500(19)30012-3","volume":"1","author":"V Kuan","year":"2019","unstructured":"Kuan, V. et al. A chronological map of 308 physical and mental health conditions from 4 million individuals in the English National Health Service. Lancet Digital Health 1, e63\u2013e77 (2019).","journal-title":"Lancet Digital Health"},{"key":"1018_CR107","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","volume":"53","author":"J Mbatchou","year":"2021","unstructured":"Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097\u20131103 (2021).","journal-title":"Nat. Genet."},{"key":"1018_CR108","doi-asserted-by":"publisher","first-page":"11484","DOI":"10.1073\/pnas.1932072100","volume":"100","author":"WJ Kent","year":"2003","unstructured":"Kent, W. J., Baertsch, R., Hinrichs, A., Miller, W. & Haussler, D. Evolution\u2019s cauldron: duplication, deletion, and rearrangement in the mouse and human genomes. Proc. Natl Acad. Sci. USA 100, 11484\u201311489 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1018_CR109","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.1093\/bioinformatics\/btq340","volume":"26","author":"CJ Willer","year":"2010","unstructured":"Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190\u20132191 (2010).","journal-title":"Bioinformatics"},{"key":"1018_CR110","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/s41588-020-0653-y","volume":"52","author":"Z Ning","year":"2020","unstructured":"Ning, Z., Pawitan, Y. & Shen, X. High-definition likelihood inference of genetic correlations across human complex traits. Nat. Genet. 52, 859\u2013864 (2020).","journal-title":"Nat. Genet."},{"key":"1018_CR111","unstructured":"Falconer, D. S. & Mackay, T. Introduction to Quantitative Genetics (Pearson, Prentice Hall, 2009)."},{"key":"1018_CR112","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.ajhg.2011.02.002","volume":"88","author":"SH Lee","year":"2011","unstructured":"Lee, S. H., Wray, N. R., Goddard, M. E. & Visscher, P. M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294\u2013305 (2011).","journal-title":"Am. J. Hum. Genet."},{"key":"1018_CR113","doi-asserted-by":"publisher","unstructured":"He, Y., Koido, M., Shimmori, Y. & Kamatani, Y. GWASLab: a Python package for processing and visualizing GWAS summary statistics. Preprint at Jxiv https:\/\/doi.org\/10.51094\/jxiv.370 (2023).","DOI":"10.51094\/jxiv.370"},{"key":"1018_CR114","doi-asserted-by":"publisher","first-page":"268","DOI":"10.7326\/M16-2607","volume":"167","author":"TJ VanderWeele","year":"2017","unstructured":"VanderWeele, T. J. & Ding, P. Sensitivity analysis in observational research: introducing the E-value. Ann. Intern. Med. 167, 268\u2013274 (2017).","journal-title":"Ann. Intern. Med."},{"key":"1018_CR115","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0154222","volume":"11","author":"DM Lyall","year":"2016","unstructured":"Lyall, D. M. et al. Cognitive Test Scores in UK Biobank: data reduction in 480,416 participants and longitudinal stability in 20,346 participants. PLoS ONE 11, e0154222 (2016).","journal-title":"PLoS ONE"},{"key":"1018_CR116","doi-asserted-by":"publisher","first-page":"e0231627","DOI":"10.1371\/journal.pone.0231627","volume":"15","author":"C Fawns-Ritchie","year":"2020","unstructured":"Fawns-Ritchie, C. & Deary, I. J. Reliability and validity of the UK Biobank cognitive tests. PLoS ONE 15, e0231627 (2020).","journal-title":"PLoS ONE"},{"key":"1018_CR117","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1017\/S0047279400020341","volume":"16","author":"P Townsend","year":"1987","unstructured":"Townsend, P. Deprivation. J. Soc. Pol. 16, 125\u2013146 (1987).","journal-title":"J. Soc. Pol."},{"key":"1018_CR118","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1093\/aje\/kwq433","volume":"173","author":"H Quan","year":"2011","unstructured":"Quan, H. et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am. J. Epidemiol. 173, 676\u2013682 (2011).","journal-title":"Am. J. Epidemiol."},{"key":"1018_CR119","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1097\/01.mlr.0000182534.19832.83","volume":"43","author":"H Quan","year":"2005","unstructured":"Quan, H. et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med. Care 43, 1130\u20131139 (2005).","journal-title":"Med. Care"},{"key":"1018_CR120","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","volume":"622","author":"BB Sun","year":"2023","unstructured":"Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329\u2013338 (2023).","journal-title":"Nature"},{"key":"1018_CR121","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform. 14, 128 (2013).","journal-title":"BMC Bioinform."},{"key":"1018_CR122","doi-asserted-by":"publisher","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","volume":"52","author":"M Milacic","year":"2024","unstructured":"Milacic, M. et al. The Reactome Pathway Knowledgebase 2024. Nucleic Acids Res. 52, D672\u2013D678 (2024).","journal-title":"Nucleic Acids Res."},{"key":"1018_CR123","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon, A. et al. The Molecular Signatures Database hallmark gene set collection. Cell Syst. 1, 417\u2013425 (2015).","journal-title":"Cell Syst."},{"key":"1018_CR124","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa, M. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27\u201330 (2000).","journal-title":"Nucleic Acids Res."},{"key":"1018_CR125","doi-asserted-by":"crossref","unstructured":"Friedman, J., Hastie, T. & Tibshirani, R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Soft. 33, 1\u201322 (2010).","DOI":"10.18637\/jss.v033.i01"},{"key":"1018_CR126","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nmeth.3945","volume":"13","author":"J Lever","year":"2016","unstructured":"Lever, J., Krzywinski, M. & Altman, N. Classification evaluation. Nat. Methods 13, 603\u2013604 (2016).","journal-title":"Nat. Methods"},{"key":"1018_CR127","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2307\/2531595","volume":"44","author":"ER DeLong","year":"1988","unstructured":"DeLong, E. R., DeLong, D. M. & Clarke-Pearson, D. L. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44, 837\u2013845 (1988).","journal-title":"Biometrics"},{"key":"1018_CR128","unstructured":"Purcell, S. M. & Chang, C. C. PLINK v.1.9 (11 Dec 2023); www.cog-genomics.org\/plink\/1.9\/"},{"key":"1018_CR129","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s43586-021-00092-5","volume":"2","author":"E Sanderson","year":"2022","unstructured":"Sanderson, E. et al. Mendelian randomization. Nat. Rev. Methods Prim. 2, 6 (2022).","journal-title":"Nat. Rev. Methods Prim."},{"key":"1018_CR130","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1001\/jama.2021.18236","volume":"326","author":"VW Skrivankova","year":"2021","unstructured":"Skrivankova, V. W. et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: the STROBE-MR statement. JAMA 326, 1614\u20131621 (2021).","journal-title":"JAMA"},{"key":"1018_CR131","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1093\/ije\/dyx028","volume":"45","author":"FP Hartwig","year":"2016","unstructured":"Hartwig, F. P., Davies, N. M., Hemani, G. & Davey Smith, G. Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int. J. Epidemiol. 45, 1717\u20131726 (2016).","journal-title":"Int. J. Epidemiol."},{"key":"1018_CR132","doi-asserted-by":"publisher","unstructured":"Bowden, J. et al. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int. J. Epidemiol. https:\/\/doi.org\/10.1093\/ije\/dyw220 (2016).","DOI":"10.1093\/ije\/dyw220"},{"key":"1018_CR133","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","volume":"37","author":"S Burgess","year":"2013","unstructured":"Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658\u2013665 (2013).","journal-title":"Genet. Epidemiol."},{"key":"1018_CR134","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34408","volume":"7","author":"G Hemani","year":"2018","unstructured":"Hemani, G. et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 7, e34408 (2018).","journal-title":"eLife"},{"key":"1018_CR135","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","volume":"44","author":"J Bowden","year":"2015","unstructured":"Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512\u2013525 (2015).","journal-title":"Int. J. Epidemiol."},{"key":"1018_CR136","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1002\/sim.6522","volume":"34","author":"FD Greco M","year":"2015","unstructured":"Greco M, F. D., Minelli, C., Sheehan, N. A. & Thompson, J. R. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat. Med. 34, 2926\u20132940 (2015).","journal-title":"Stat. Med."},{"key":"1018_CR137","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1093\/ije\/dyy258","volume":"48","author":"J Bowden","year":"2019","unstructured":"Bowden, J. et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int. J. Epidemiol. 48, 728\u2013742 (2019).","journal-title":"Int. J. Epidemiol."},{"key":"1018_CR138","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1093\/bioinformatics\/btv546","volume":"32","author":"T Berisa","year":"2016","unstructured":"Berisa, T. & Pickrell, J. K. Approximately independent linkage disequilibrium blocks in human populations. Bioinformatics 32, 283\u2013285 (2016).","journal-title":"Bioinformatics"},{"key":"1018_CR139","doi-asserted-by":"publisher","first-page":"e1004219","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."}],"container-title":["Nature Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01018-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01018-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01018-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:02:49Z","timestamp":1769000569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43587-025-01018-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":139,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["1018"],"URL":"https:\/\/doi.org\/10.1038\/s43587-025-01018-6","relation":{},"ISSN":["2662-8465"],"issn-type":[{"value":"2662-8465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]},"assertion":[{"value":"11 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2025","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","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}