{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:17:31Z","timestamp":1789996651183,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:00:00Z","timestamp":1671408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council (Australia)","doi-asserted-by":"publisher","award":["APP1161706"],"award-info":[{"award-number":["APP1161706"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council (Australia)","doi-asserted-by":"publisher","award":["APP1191535"],"award-info":[{"award-number":["APP1191535"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, the mechanisms underlying their relationships remain unclear. Leveraging large-scale genome-wide association studies\u2019 summary statistics, we comprehensively assessed genetic overlap and potential causality of cognitive traits and Alzheimer\u2019s disease (AD) with several GIT disorders. We demonstrate a strong and highly significant inverse global genetic correlation between cognitive traits and GIT disorders\u2014peptic ulcer disease (PUD), gastritis-duodenitis, diverticulosis, irritable bowel syndrome, and gastroesophageal reflux disease (GERD), but not inflammatory bowel disease (IBD). Further analysis detects 35 significant (p &lt; 4.37 \u00d7 10\u22125) bivariate local genetic correlations between cognitive traits, AD, and GIT disorders (including IBD). Mendelian randomisation analysis suggests a risk-decreasing causality of educational attainment, intelligence, and other cognitive traits on PUD and GERD, but not IBD, and a putative association of GERD with cognitive function decline. Gene-based analysis reveals a significant gene-level genetic overlap of cognitive traits with AD and GIT disorders (IBD inclusive, pbinomial-test\u2009=\u20091.18 \u00d7 10\u22123\u20132.20 \u00d7 10\u221216). Our study supports the protective roles of genetically-influenced educational attainments and other cognitive traits on the risk of GIT disorders and highlights a putative association of GERD with cognitive function decline. Findings from local genetic correlation analysis provide novel insights, indicating that the relationship of IBD with cognitive traits (and AD) will depend largely on their local effects across the genome.<\/jats:p>","DOI":"10.3390\/ijms232416199","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T05:25:46Z","timestamp":1671427546000},"page":"16199","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Relationship of Cognition and Alzheimer\u2019s Disease with Gastrointestinal Tract Disorders: A Large-Scale Genetic Overlap and Mendelian Randomisation Analysis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-0340","authenticated-orcid":false,"given":"Emmanuel O.","family":"Adewuyi","sequence":"first","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor K.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenielle","family":"Porter","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"},{"name":"Curtin Medical School, Curtin University, Bentley, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-7082","authenticated-orcid":false,"given":"Simon M.","family":"Laws","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA 6027, Australia"},{"name":"Curtin Medical School, Curtin University, Bentley, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120088","DOI":"10.1016\/j.lfs.2021.120088","article-title":"Does Alzheimer\u2019s disease stem in the gastrointestinal system?","volume":"287","author":"Khodabakhsh","year":"2021","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Singh, A., Dawson, T.M., and Kulkarni, S. (2021). Neurodegenerative disorders and gut-brain interactions. J. Clin. Investig., 131.","DOI":"10.1172\/JCI143775"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mitrea, L., Nemes, S.A., Szabo, K., Teleky, B.E., and Vodnar, D.C. (2022). Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders. Front. Med.","DOI":"10.3389\/fmed.2022.813204"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nn.4476","article-title":"Interactions between the microbiota, immune and nervous systems in health and disease","volume":"20","author":"Fung","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5026","DOI":"10.1007\/s12035-020-02073-3","article-title":"Gut Microbiota and Dysbiosis in Alzheimer\u2019s Disease: Implications for Pathogenesis and Treatment","volume":"57","author":"Liu","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lee, J.-G., Cho, H.-J., Jeong, Y.-M., and Lee, J.-S. (2021). Genetic Approaches Using Zebrafish to Study the Microbiota\u2013Gut\u2013Brain Axis in Neurological Disorders. Cells, 10.","DOI":"10.3390\/cells10030566"},{"key":"ref_7","first-page":"1","article-title":"A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer\u2019s disease and gastrointestinal tract disorders","volume":"5","author":"dewuyi","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JAD-161141","article-title":"The Gut Microbiota and Alzheimer\u2019s Disease","volume":"58","author":"Jiang","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1080\/00207454.2020.1738432","article-title":"Alzheimer\u2019s disease and gastrointestinal microbiota; impact of Helicobacter pylori infection involvement","volume":"131","author":"Doulberis","year":"2020","journal-title":"Int. J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1177\/1533317513518654","article-title":"Gastritis May Boost Odds of Dementia","volume":"29","author":"Momtaz","year":"2014","journal-title":"Am. J. Alzheimer\u2019s Dis. Other Dementiasr"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Gau, S.-Y., Lai, J.-N., Yip, H.-T., Wu, M.-C., and Wei, J.C.-C. (2022). Higher Dementia Risk in People With Gastroesophageal Reflux Disease: A Real-World Evidence. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.830729"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1136\/gutjnl-2020-320789","article-title":"Inflammatory bowel disease is associated with higher dementia risk: A nationwide longitudinal study","volume":"70","author":"Zhang","year":"2020","journal-title":"Gut"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0144589","DOI":"10.1371\/journal.pone.0144589","article-title":"Irritable Bowel Syndrome Is Associated with an Increased Risk of Dementia: A Nationwide Population-Based Study","volume":"11","author":"Chen","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1177\/1533317515617546","article-title":"Association of Dementia and Peptic Ulcer Disease","volume":"31","author":"Hsu","year":"2016","journal-title":"Am. J. Alzheimer\u2019s Dis. Other Dementiasr"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-022-02478-y","article-title":"Regular proton pump inhibitor use and incident dementia: Population-based cohort study","volume":"20","author":"Zhang","year":"2022","journal-title":"BMC Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4209","DOI":"10.1113\/JP279919","article-title":"Intra-gastrointestinal amyloid-\u03b21\u201342 oligomers perturb enteric function and induce Alzheimer's disease pathology","volume":"598","author":"Sun","year":"2020","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1113\/JP280624","article-title":"Gut amyloid-\u03b2 induces cognitive deficits and Alzheimer's disease-related histopathology in a mouse model","volume":"599","author":"Vonderwalde","year":"2020","journal-title":"J. Physiol."},{"key":"ref_18","unstructured":"Prince, M., Wimo, A., Guerchet, M., Ali, G.C., Wu, Y.T., and Prina, M. (2015). World Alzheimer Report 2015: The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends, Alzheimer\u2019s Disease International."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.trci.2019.05.008","article-title":"Alzheimer\u2019s disease drug development pipeline: 2019","volume":"5","author":"Cummings","year":"2019","journal-title":"Alzheimer\u2019s Dementia Transl. Res. Clin. Interv."},{"key":"ref_20","first-page":"387","article-title":"Cognitive Impairment in Adult Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis","volume":"62","author":"Hopkins","year":"2021","journal-title":"Psychosom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.parkreldis.2020.01.009","article-title":"Gastrointestinal symptoms are predictive of trajectories of cognitive functioning in de novo Parkinson's disease","volume":"72","author":"Jones","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"ref_22","first-page":"1","article-title":"Impaired neurocognitive and psychomotor performance in patients with inflammatory bowel disease","volume":"9","author":"Hadjina","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s12664-020-01122-y","article-title":"Cognitive dysfunction in ulcerative colitis patients in remission and its comparison with patients with irritable bowel syndrome and healthy controls","volume":"40","author":"Sharma","year":"2021","journal-title":"Indian J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Patrick, K.S., Sanborn, V., Gunstad, J., and Spitznagel, M.B. (2022). Poorer Cognitive Performance Is Associated with Gastrointestinal Symptoms in Otherwise Healthy Young Adults. Dig. Dis., 1\u20136.","DOI":"10.1159\/000523865"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(16)32404-7","article-title":"Peptic ulcer disease","volume":"390","author":"Lanas","year":"2017","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.jfma.2017.11.005","article-title":"Association between Helicobacter pylori infection and cognitive impairment in the elderly","volume":"117","author":"Han","year":"2018","journal-title":"J. Formos. Med Assoc."},{"key":"ref_27","first-page":"426","article-title":"Microbes and Alzheimer\u2019 disease: Lessons from H. pylori and GUT microbiota","volume":"23","author":"Franceschi","year":"2019","journal-title":"Eur. Rev. Med Pharmacol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.jalz.2019.07.002","article-title":"Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota","volume":"15","author":"Li","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_29","first-page":"1","article-title":"GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression","volume":"12","author":"Wu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.neurobiolaging.2015.10.039","article-title":"The inflammatory markers CRP, IL-6, and IL-10 are associated with cognitive function\u2014Data from the Berlin Aging Study II","volume":"38","author":"Tegeler","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"918-e704","DOI":"10.1111\/nmo.12219","article-title":"An observational study of cognitive function in patients with irritable bowel syndrome and inflammatory bowel disease","volume":"25","author":"Berrill","year":"2013","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.brainres.2019.05.036","article-title":"Cognitive impairment in Irritable Bowel Syndrome (IBS): A systematic review","volume":"1719","author":"Lam","year":"2019","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Loh","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Hemani, G., Zheng, J., Elsworth, B., Wade, K.H., Haberland, V., Baird, D., Laurin, C., Burgess, S., Bowden, J., and Langdon, R. (2018). The MR-Base platform supports systematic causal inference across the human phenome. Elife, 7.","DOI":"10.7554\/eLife.34408"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41588-022-01017-y","article-title":"An integrated framework for local genetic correlation analysis","volume":"54","author":"Werme","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_37","first-page":"1163","article-title":"Education, intelligence and Alzheimer\u2019s disease: Evidence from a multivariable two-sample Mendelian randomization study","volume":"49","author":"Anderson","year":"2020","journal-title":"Leuk. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"j3542","DOI":"10.1136\/bmj.j3542","article-title":"Education and coronary heart disease: Mendelian randomisation study","volume":"358","author":"Tillmann","year":"2017","journal-title":"BMJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/apt.17119","article-title":"Risk of dementia in patients with inflammatory bowel disease: A Danish population-based study","volume":"56","author":"Sand","year":"2022","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sun, Y., Geng, J., Chen, X., Chen, H., Wang, X., Chen, J., Li, X., and Hesketh, T. (2021). Association Between Inflammatory Bowel Disease and Dementia: A Longitudinal Cohort Study. Inflamm. Bowel Dis.","DOI":"10.1093\/ibd\/izab300"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1111\/apt.16444","article-title":"Comorbidity before and after a diagnosis of inflammatory bowel disease","volume":"54","author":"Bernstein","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s41588-018-0152-6","article-title":"Faculty Opinions recommendation of Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence","volume":"50","author":"Savage","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/s41588-018-0147-3","article-title":"Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals","volume":"50","author":"Lee","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1038\/s41588-019-0481-0","article-title":"A global overview of pleiotropy and genetic architecture in complex traits","volume":"51","author":"Watanabe","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_45","first-page":"1","article-title":"Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases","volume":"10","author":"An","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1681\/ASN.2016010098","article-title":"Mendelian Randomization as an Approach to Assess Causality Using Observational Data","volume":"27","author":"Sekula","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_48","unstructured":"Wooldridge, J.M. (2009). Chapter 15: Instrumental Variables Estimation and Two-stage Least Squares. Introductory econometrics, South-Western Publishing."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/s41431-018-0150-2","article-title":"Molecular genetic overlap between migraine and major depressive disorder","volume":"26","author":"Yang","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s00439-016-1755-6","article-title":"Gene-based analyses reveal novel genetic overlap and allelic heterogeneity across five major psychiatric disorders","volume":"136","author":"Zhao","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1093\/humrep\/deab254","article-title":"Genetic overlap analysis of endometriosis and asthma identifies shared loci implicating sex hormones and thyroid signalling pathways","volume":"37","author":"Adewuyi","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00439-020-02223-6","article-title":"Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality","volume":"140","author":"Adewuyi","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Adewuyi, E.O., Sapkota, Y., International Endogene Consortium (IEC) International Endogene Consortium (IEC), 23andMe Research Team 23andMe Research Team, International Headache Genetics Consortium (IHGC) International Headache Genetics Consortium (IHGC), Auta, A., Yoshihara, K., Nyegaard, M., Griffiths, L.R., and Montgomery, G.W. (2020). Shared Molecular Genetic Mechanisms Underlie Endometriosis and Migraine Comorbidity. Genes, 11.","DOI":"10.3390\/genes11030268"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-022-30184-z","article-title":"The International Headache Genetics Consortium Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt\/\u03b2-catenin signalling in migraine","volume":"13","author":"Tanha","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"de Leeuw, C.A., Mooij, J.M., Heskes, T., and Posthuma, D. (2015). MAGMA: Generalized Gene-Set Analysis of GWAS Data. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16199\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:44:05Z","timestamp":1760147045000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16199"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,19]]},"references-count":59,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232416199"],"URL":"https:\/\/doi.org\/10.3390\/ijms232416199","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-1931535\/v2","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,19]]}}}