{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:37:14Z","timestamp":1786628234032,"version":"build-2736575974"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":79,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32500519"],"award-info":[{"award-number":["32500519"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82088102, 81970691, 81970728, 81930021 and 81941017"],"award-info":[{"award-number":["82088102, 81970691, 81970728, 81930021 and 81941017"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32570728"],"award-info":[{"award-number":["32570728"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shanghai Municipal Education Commission\u2013Gaofeng Clinical Medicine Grant Support","award":["20161307 and 20152508 Round 2"],"award-info":[{"award-number":["20161307 and 20152508 Round 2"]}]},{"name":"Lingang laboratory","award":["LGL-2616-01"],"award-info":[{"award-number":["LGL-2616-01"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2024ZD0531500, 2024ZD0531502, 2024ZD0531506"],"award-info":[{"award-number":["2024ZD0531500, 2024ZD0531502, 2024ZD0531506"]}]},{"name":"National Key Research and Development Program of China","award":["2022YFC2505203"],"award-info":[{"award-number":["2022YFC2505203"]}]},{"name":"Shanghai ZhangJiang Talent Programe","award":["RC20240007"],"award-info":[{"award-number":["RC20240007"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"DOI":"10.1186\/s12916-026-04888-8","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T05:45:13Z","timestamp":1779774313000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis"],"prefix":"10.1186","volume":"24","author":[{"given":"Zhihe","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiling","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanhui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangbo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiange","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieli","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"4888_CR1","doi-asserted-by":"publisher","first-page":"100028","DOI":"10.1016\/j.glmedi.2023.100028","volume":"1","author":"JH Jaradat","year":"2023","unstructured":"Jaradat JH, Nashwan AJ. Cardiovascular-kidney-metabolic syndrome: Understanding the interconnections and the need for holistic intervention. J Med Surg Public Health. 2023;1:100028.","journal-title":"J Med Surg Public Health"},{"issue":"4","key":"4888_CR2","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1136\/gutjnl-2023-330595","volume":"73","author":"G Targher","year":"2024","unstructured":"Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024;73(4):691\u2013702.","journal-title":"Gut"},{"issue":"1","key":"4888_CR3","doi-asserted-by":"publisher","first-page":"101506","DOI":"10.1016\/j.diabet.2023.101506","volume":"50","author":"J Bilson","year":"2024","unstructured":"Bilson J, Mantovani A, Byrne CD, Targher G. Steatotic liver disease, MASLD and risk of chronic kidney disease. Diabetes Metab. 2024;50(1):101506.","journal-title":"Diabetes Metab"},{"issue":"20","key":"4888_CR4","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1161\/CIR.0000000000001184","volume":"148","author":"CE Ndumele","year":"2023","unstructured":"Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, et al. Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association. Circulation. 2023;148(20):1606\u201335.","journal-title":"Circulation"},{"issue":"7","key":"4888_CR5","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.2337\/dci24-0094","volume":"48","author":"K Cusi","year":"2025","unstructured":"Cusi K, Abdelmalek MF, Apovian CM, Balapattabi K, Bannuru RR, Barb D, et al. Metabolic Dysfunction\u2013Associated Steatotic Liver Disease (MASLD) in People With Diabetes: The Need for Screening and Early Intervention. A Consensus Report of the American Diabetes Association. Diabetes Care. 2025;48(7):1057\u201382.","journal-title":"Diabetes Care"},{"issue":"20","key":"4888_CR6","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1161\/CIR.0000000000001186","volume":"148","author":"CE Ndumele","year":"2023","unstructured":"Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, Mathew RO, Khan SS, et al. A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association. Circulation. 2023;148(20):1636\u201364.","journal-title":"Circulation"},{"key":"4888_CR7","doi-asserted-by":"publisher","first-page":"101102","DOI":"10.1016\/j.molmet.2020.101102","volume":"46","author":"MA Nauck","year":"2021","unstructured":"Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102.","journal-title":"Mol Metab"},{"issue":"2","key":"4888_CR8","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1210\/jc.2014-3415","volume":"100","author":"CM Apovian","year":"2015","unstructured":"Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342\u201362.","journal-title":"J Clin Endocrinol Metab"},{"key":"4888_CR9","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.pcad.2021.09.007","volume":"68","author":"R Aggarwal","year":"2021","unstructured":"Aggarwal R, Vaduganathan M, Chiu N, Bhatt DL. Potential implications of the FDA approval of semaglutide for overweight and obese adults in the United States. Prog Cardiovasc Dis. 2021;68:97\u20138.","journal-title":"Prog Cardiovasc Dis"},{"issue":"3","key":"4888_CR10","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/s41574-022-00776-2","volume":"19","author":"LL Lim","year":"2023","unstructured":"Lim LL, Chow E, Chan JCN. Cardiorenal diseases in type 2 diabetes mellitus: clinical trials and real-world practice. Nat Rev Endocrinol. 2023;19(3):151\u201363.","journal-title":"Nat Rev Endocrinol"},{"issue":"10454","key":"4888_CR11","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/S0140-6736(24)01498-3","volume":"404","author":"J Deanfield","year":"2024","unstructured":"Deanfield J, Verma S, Scirica BM, Kahn SE, Emerson SS, Ryan D, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet. 2024;404(10454):773\u201386.","journal-title":"Lancet"},{"issue":"21","key":"4888_CR12","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","volume":"392","author":"AJ Sanyal","year":"2025","unstructured":"Sanyal AJ, Newsome PN, Kliers I, \u00d8stergaard LH, Long MT, Kj\u00e6r MS, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025;392(21):2089\u201399.","journal-title":"N Engl J Med"},{"issue":"1","key":"4888_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","volume":"32","author":"GD Smith","year":"2003","unstructured":"Smith GD, Ebrahim S. Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1\u201322.","journal-title":"Int J Epidemiol"},{"issue":"11","key":"4888_CR14","doi-asserted-by":"publisher","first-page":"2718","DOI":"10.2337\/dc22-0323","volume":"45","author":"M Xu","year":"2022","unstructured":"Xu M, Zheng J, Hou T, Lin H, Wang T, Wang S, et al. SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study. Diabetes Care. 2022;45(11):2718\u201328.","journal-title":"Diabetes Care"},{"issue":"8","key":"4888_CR15","doi-asserted-by":"publisher","first-page":"4688","DOI":"10.1097\/JS9.0000000000001514","volume":"110","author":"Y Sun","year":"2024","unstructured":"Sun Y, Liu Y, Dian Y, Zeng F, Deng G, Lei S. Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials. Int J Surg Lond Engl. 2024;110(8):4688\u201394.","journal-title":"Int J Surg Lond Engl"},{"issue":"13","key":"4888_CR16","doi-asserted-by":"publisher","first-page":"e020331","DOI":"10.1161\/JAHA.120.020331","volume":"10","author":"I Daghlas","year":"2021","unstructured":"Daghlas I, Karhunen V, Ray D, Zuber V, Burgess S, Tsao PS, et al. Genetic Evidence for Repurposing of GLP1R (Glucagon-Like Peptide\u20101 Receptor) Agonists to Prevent Heart Failure. J Am Heart Assoc Cardiovasc Cerebrovasc Dis. 2021;10(13):e020331.","journal-title":"J Am Heart Assoc Cardiovasc Cerebrovasc Dis"},{"issue":"6","key":"4888_CR17","first-page":"1866","volume":"45","author":"DA Lawlor","year":"2016","unstructured":"Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol. 2016;45(6):1866\u201386.","journal-title":"Int J Epidemiol"},{"issue":"6509","key":"4888_CR18","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1126\/science.aaz1776","volume":"369","author":"The GTEx Consortium","year":"2020","unstructured":"The GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318\u201330.","journal-title":"Science"},{"key":"4888_CR19","unstructured":"The GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. GTEx https:\/\/gtexportal.org\/home\/downloads (2020)."},{"issue":"7726","key":"4888_CR20","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203\u20139.","journal-title":"Nature"},{"issue":"7982","key":"4888_CR21","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","volume":"622","author":"BB Sun","year":"2023","unstructured":"Sun BB, Chiou J, Traylor M, Benner C, Hsu YH, Richardson TG, et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature. 2023;622(7982):329\u201338.","journal-title":"Nature"},{"issue":"3","key":"4888_CR22","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.pharmthera.2006.11.007","volume":"113","author":"ME Doyle","year":"2007","unstructured":"Doyle ME, Egan JM. Mechanisms of Action of GLP-1 in the Pancreas. Pharmacol Ther. 2007;113(3):546\u201393.","journal-title":"Pharmacol Ther"},{"issue":"4","key":"4888_CR23","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1214\/20-AOS2027","volume":"49","author":"T Ye","year":"2021","unstructured":"Ye T, Shao J, Kang H. Debiased inverse-variance weighted estimator in two-sample summary-data Mendelian randomization. Ann Stat. 2021;49(4):2079\u2013100.","journal-title":"Ann Stat"},{"issue":"2","key":"4888_CR24","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.kint.2019.10.027","volume":"97","author":"A K\u00f6ttgen","year":"2020","unstructured":"K\u00f6ttgen A, Pattaro C. The CKDGen Consortium: ten years of insights into the genetic basis of kidney function. Kidney Int. 2020;97(2):236\u201342.","journal-title":"Kidney Int"},{"issue":"6","key":"4888_CR25","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1038\/s41588-019-0407-x","volume":"51","author":"M Wuttke","year":"2019","unstructured":"Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nat Genet. 2019;51(6):957\u201372.","journal-title":"Nat Genet"},{"key":"4888_CR26","unstructured":"Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. CKDGen https:\/\/ckdgen.imbi.uni-freiburg.de\/datasets\/Wuttke_2019 (2019)."},{"issue":"10","key":"4888_CR27","doi-asserted-by":"publisher","first-page":"4130","DOI":"10.1038\/s41467-019-11576-0","volume":"1","author":"A Teumer","year":"2019","unstructured":"Teumer A, Li Y, Ghasemi S, Prins BP, Wuttke M, Hermle T et al. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nat Commun. 2019;10(1):4130.","journal-title":"Nat Commun"},{"key":"4888_CR28","unstructured":"Teumer A, Li Y, Ghasemi S, Prins BP, Wuttke M, Hermle T et al. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. CKDGen https:\/\/ckdgen.imbi.uni-freiburg.de\/datasets\/Teumer_2019 (2019)."},{"issue":"1","key":"4888_CR29","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41467-019-13690-5","volume":"11","author":"S Shah","year":"2020","unstructured":"Shah S, Henry A, Roselli C, Lin H, Sveinbj\u00f6rnsson G, Fatemifar G, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun. 2020;11(1):163.","journal-title":"Nat Commun"},{"key":"4888_CR30","unstructured":"Shah S, Henry A, Roselli C, Lin H, Sveinbj\u00f6rnsson G, Fatemifar G, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Cardiovascular Disease Knowledge Portal https:\/\/cvd.hugeamp.org\/downloads.html (2020)."},{"issue":"12","key":"4888_CR31","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1038\/s41588-022-01233-6","volume":"54","author":"KG Aragam","year":"2022","unstructured":"Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 2022;54(12):1803\u201315.","journal-title":"Nat Genet"},{"key":"4888_CR32","unstructured":"Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. CARDIoGRAMplusC4D https:\/\/cardiogramplusc4d.org\/data-downloads\/ (2022)."},{"issue":"4","key":"4888_CR33","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1038\/s41588-024-02064-3","volume":"57","author":"A Henry","year":"2025","unstructured":"Henry A, Mo X, Finan C, Chaffin MD, Speed D, Issa H, et al. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Nat Genet. 2025;57(4):815\u201328.","journal-title":"Nat Genet"},{"key":"4888_CR34","unstructured":"Henry A, Mo X, Finan C, Chaffin MD, Speed D, Issa H, et al. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes. Cardiovascular Disease Knowledge Portal https:\/\/cvd.hugeamp.org\/downloads.html (2024)."},{"issue":"6","key":"4888_CR35","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1038\/s41588-021-00852-9","volume":"53","author":"J Chen","year":"2021","unstructured":"Chen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan J, et al. The trans-ancestral genomic architecture of glycemic traits. Nat Genet. 2021;53(6):840\u201360.","journal-title":"Nat Genet"},{"key":"4888_CR36","unstructured":"Chen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan J, et al. The trans-ancestral genomic architecture of glycemic traits. MAGIC https:\/\/www.magicinvestigators.org\/downloads\/index.html (2021)."},{"issue":"8003","key":"4888_CR37","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","volume":"627","author":"K Suzuki","year":"2024","unstructured":"Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature. 2024;627(8003):347\u201357.","journal-title":"Nature"},{"key":"4888_CR38","unstructured":"Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. DIAGRAM http:\/\/www.diagram-consortium.org\/downloads.html (2024)."},{"issue":"1","key":"4888_CR39","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/hmg\/ddy327","volume":"28","author":"SL Pulit","year":"2019","unstructured":"Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet. 2019;28(1):166\u201374.","journal-title":"Hum Mol Genet"},{"key":"4888_CR40","doi-asserted-by":"crossref","unstructured":"Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Zenodo https:\/\/zenodo.org\/records\/1251813 (2018).","DOI":"10.1093\/hmg\/ddy327"},{"issue":"3","key":"4888_CR41","doi-asserted-by":"publisher","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","volume":"12","author":"C Sudlow","year":"2015","unstructured":"Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, 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. 2015;12(3):e1001779.","journal-title":"PLoS Med"},{"key":"4888_CR42","unstructured":"Elsworth B, Lyon M, Alexander T, Liu Y, Matthews P, Hallett J, et al. The MRC IEU OpenGWAS data infrastructure. IEU OpenGWAS https:\/\/opengwas.io\/datasets\/ukb-b-11842 (2018)."},{"issue":"3","key":"4888_CR43","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1002\/sim.6358","volume":"34","author":"NM Davies","year":"2015","unstructured":"Davies NM, von Hinke Kessler Scholder S, Farbmacher H, Burgess S, Windmeijer F, Smith GD. The many weak instruments problem and Mendelian randomization. Stat Med. 2015;34(3):454\u201368.","journal-title":"Stat Med"},{"issue":"9","key":"4888_CR44","doi-asserted-by":"publisher","first-page":"e0222362","DOI":"10.1371\/journal.pone.0222362","volume":"14","author":"JMB Rees","year":"2019","unstructured":"Rees JMB, Wood AM, Dudbridge F, Burgess S. Robust methods in Mendelian randomization via penalization of heterogeneous causal estimates. PLoS ONE. 2019;14(9):e0222362.","journal-title":"PLoS ONE"},{"issue":"3","key":"4888_CR45","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1214\/19-AOS1866","volume":"48","author":"Q Zhao","year":"2020","unstructured":"Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Ann Stat. 2020;48(3):1742\u201369.","journal-title":"Ann Stat"},{"issue":"4","key":"4888_CR46","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1002\/gepi.22551","volume":"48","author":"A Patel","year":"2024","unstructured":"Patel A, Gill D, Shungin D, Mantzoros CS, Knudsen LB, Bowden J, et al. Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region. Genet Epidemiol. 2024;48(4):151\u201363.","journal-title":"Genet Epidemiol"},{"issue":"4","key":"4888_CR47","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1177\/0962280206077743","volume":"16","author":"V Didelez","year":"2007","unstructured":"Didelez V, Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res. 2007;16(4):309\u201330.","journal-title":"Stat Methods Med Res"},{"issue":"11","key":"4888_CR48","doi-asserted-by":"publisher","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","volume":"13","author":"G Hemani","year":"2017","unstructured":"Hemani G, Tilling K, Smith GD. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLOS Genet. 2017;13(11):e1007081.","journal-title":"PLOS Genet"},{"key":"4888_CR49","doi-asserted-by":"crossref","unstructured":"Elsworth B, Lyon M, Alexander T, Liu Y, Matthews P, Hallett J et al. The MRC IEU OpenGWAS data infrastructure. bioRxiv. 2020 Aug.","DOI":"10.1101\/2020.08.10.244293"},{"issue":"7877","key":"4888_CR50","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/s41586-021-03855-y","volume":"597","author":"Q Wang","year":"2021","unstructured":"Wang Q, Dhindsa RS, Carss K, Harper AR, Nag A, Tachmazidou I, et al. Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature. 2021;597(7877):527\u201332.","journal-title":"Nature"},{"issue":"16","key":"4888_CR51","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1001\/jama.2021.18236","volume":"326","author":"VW Skrivankova","year":"2021","unstructured":"Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326(16):1614\u201321.","journal-title":"JAMA"},{"key":"4888_CR52","doi-asserted-by":"publisher","first-page":"n2233","DOI":"10.1136\/bmj.n2233","volume":"375","author":"VW Skrivankova","year":"2021","unstructured":"Skrivankova VW, Richmond RC, Woolf BAR, Davies NM, Swanson SA, VanderWeele TJ, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021;375:n2233.","journal-title":"BMJ"},{"issue":"1","key":"4888_CR53","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1471-230X-6-33","volume":"6","author":"G Bedogni","year":"2006","unstructured":"Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6(1):33.","journal-title":"BMC Gastroenterol"},{"issue":"11","key":"4888_CR54","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1016\/j.medj.2024.07.013","volume":"5","author":"F Jiang","year":"2024","unstructured":"Jiang F, Wang L, Ying H, Sun J, Zhao J, Lu Y, et al. Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease. Med. 2024;5(11):1413\u2013e14233.","journal-title":"Med"},{"issue":"11","key":"4888_CR55","doi-asserted-by":"publisher","first-page":"100437","DOI":"10.1016\/j.xcrm.2021.100437","volume":"2","author":"N Ghodsian","year":"2021","unstructured":"Ghodsian N, Abner E, Emdin CA, Gobeil \u00c9, Taba N, Haas ME, et al. Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease. Cell Rep Med. 2021;2(11):100437.","journal-title":"Cell Rep Med"},{"issue":"7","key":"4888_CR56","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","volume":"53","author":"J Mbatchou","year":"2021","unstructured":"Mbatchou J, Barnard L, Backman J, Marcketta A, Kosmicki JA, Ziyatdinov A, et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet. 2021;53(7):1097\u2013103.","journal-title":"Nat Genet"},{"issue":"4","key":"4888_CR57","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/ng.2213","volume":"44","author":"J Yang","year":"2012","unstructured":"Yang J, Ferreira T, Morris AP, Medland SE, Madden PAF, Heath AC, et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat Genet. 2012;44(4):369\u201375.","journal-title":"Nat Genet"},{"issue":"1","key":"4888_CR58","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","volume":"88","author":"J Yang","year":"2011","unstructured":"Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011;88(1):76\u201382.","journal-title":"Am J Hum Genet"},{"issue":"3","key":"4888_CR59","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","volume":"47","author":"BK Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J, Patterson N, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47(3):291\u20135.","journal-title":"Nat Genet"},{"issue":"11","key":"4888_CR60","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ng.3406","volume":"47","author":"B Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh PR, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47(11):1236\u201341.","journal-title":"Nat Genet"},{"issue":"1","key":"4888_CR61","doi-asserted-by":"publisher","first-page":"1826","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. 2017;8(1):1826.","journal-title":"Nat Commun"},{"issue":"7","key":"4888_CR62","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"4888_CR63","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters. OMICS J Integr Biol. 2012;16(5):284\u20137.","journal-title":"OMICS J Integr Biol"},{"issue":"3","key":"4888_CR64","doi-asserted-by":"publisher","first-page":"e221169","DOI":"10.1001\/jamanetworkopen.2022.1169","volume":"5","author":"JJ Chen","year":"2022","unstructured":"Chen JJ, Wu CY, Jenq CC, Lee TH, Tsai CY, Tu HT, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist vs Dipeptidyl Peptidase-4 Inhibitor Use With Mortality Among Patients With Type 2 Diabetes and Advanced Chronic Kidney Disease. JAMA Netw Open. 2022;5(3):e221169.","journal-title":"JAMA Netw Open"},{"issue":"2","key":"4888_CR65","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1056\/NEJMoa2403347","volume":"391","author":"V Perkovic","year":"2024","unstructured":"Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024;391(2):109\u201321.","journal-title":"N Engl J Med"},{"issue":"10","key":"4888_CR66","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/S2213-8587(19)30249-9","volume":"7","author":"SL Kristensen","year":"2019","unstructured":"Kristensen SL, R\u00f8rth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776\u201385.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"4888_CR67","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.clinthera.2022.12.006","volume":"45","author":"L Huixing","year":"2023","unstructured":"Huixing L, Di F, Daoquan P. Effect of Glucagon-like Peptide-1 Receptor Agonists on Prognosis of Heart Failure and Cardiac Function: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Ther. 2023;45(1):17\u201330.","journal-title":"Clin Ther"},{"issue":"12","key":"4888_CR68","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1056\/NEJMoa2306963","volume":"389","author":"MN Kosiborod","year":"2023","unstructured":"Kosiborod MN, Abildstr\u00f8m SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069\u201384.","journal-title":"N Engl J Med"},{"issue":"1","key":"4888_CR69","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s12933-020-0987-x","volume":"19","author":"DP Zhang","year":"2020","unstructured":"Zhang DP, Xu L, Wang LF, Wang HJ, Jiang F. Effects of antidiabetic drugs on left ventricular function\/dysfunction: a systematic review and network meta-analysis. Cardiovasc Diabetol. 2020;19(1):10.","journal-title":"Cardiovasc Diabetol"},{"issue":"5","key":"4888_CR70","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1001\/jama.2016.10260","volume":"316","author":"KB Margulies","year":"2016","unstructured":"Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;316(5):500\u20138.","journal-title":"JAMA"},{"issue":"10","key":"4888_CR71","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1056\/NEJMoa2302392","volume":"389","author":"S Wharton","year":"2023","unstructured":"Wharton S, Blevins T, Connery L, Rosenstock J, Raha S, Liu R, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023;389(10):877\u201388.","journal-title":"N Engl J Med"},{"issue":"1","key":"4888_CR72","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s12872-020-01384-6","volume":"20","author":"KE Kurgansky","year":"2020","unstructured":"Kurgansky KE, Schubert P, Parker R, Djousse L, Riebman JB, Gagnon DR, et al. Association of pulse rate with outcomes in heart failure with reduced ejection fraction: a retrospective cohort study. BMC Cardiovasc Disord. 2020;20(1):92.","journal-title":"BMC Cardiovasc Disord"},{"issue":"1","key":"4888_CR73","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s12933-014-0142-7","volume":"13","author":"FK Saraiva","year":"2014","unstructured":"Saraiva FK, Sposito AC. Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc Diabetol. 2014;13(1):142.","journal-title":"Cardiovasc Diabetol"},{"issue":"12","key":"4888_CR74","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1016\/j.jacbts.2024.07.006","volume":"9","author":"MD Martens","year":"2024","unstructured":"Martens MD, Abuetabh Y, Schmidt MA, Zolondek MCP, Silver HL, Levasseur JL, et al. Semaglutide Reduces Cardiomyocyte Size and Cardiac Mass in Lean and Obese Mice. JACC Basic Transl Sci. 2024;9(12):1429\u201331.","journal-title":"JACC Basic Transl Sci"},{"issue":"1","key":"4888_CR75","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jhep.2024.07.006","volume":"82","author":"SA Harrison","year":"2025","unstructured":"Harrison SA, Browne SK, Suschak JJ, Tomah S, Gutierrez JA, Yang J, et al. Effect of pemvidutide, a GLP-1\/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study. J Hepatol. 2025;82(1):7\u201317.","journal-title":"J Hepatol"},{"issue":"11","key":"4888_CR76","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1001\/jamainternmed.2024.4661","volume":"184","author":"F Kanwal","year":"2024","unstructured":"Kanwal F, Kramer JR, Li L, Yang YX, Cao Y, Yu X, et al. GLP-1 Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. JAMA Intern Med. 2024;184(11):1314\u201323.","journal-title":"JAMA Intern Med"},{"issue":"1","key":"4888_CR77","first-page":"47","volume":"13","author":"MW Wang","year":"2025","unstructured":"Wang MW, Lu LG. Current Status of Glucagon-like Peptide-1 Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: A Clinical Perspective. J Clin Transl Hepatol. 2025;13(1):47\u201361.","journal-title":"J Clin Transl Hepatol"},{"issue":"6","key":"4888_CR78","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/s41588-022-01078-z","volume":"54","author":"M Vujkovic","year":"2022","unstructured":"Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, et al. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nat Genet. 2022;54(6):761\u201371.","journal-title":"Nat Genet"},{"issue":"2","key":"4888_CR79","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/hep4.1805","volume":"6","author":"CJ Fairfield","year":"2022","unstructured":"Fairfield CJ, Drake TM, Pius R, Bretherick AD, Campbell A, Clark DW, et al. Genome-Wide Association Study of NAFLD Using Electronic Health Records. Hepatol Commun. 2022;6(2):297.","journal-title":"Hepatol Commun"},{"issue":"5","key":"4888_CR80","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/s41588-024-01720-y","volume":"56","author":"J Ghouse","year":"2024","unstructured":"Ghouse J, Sveinbj\u00f6rnsson G, Vujkovic M, Seidelin AS, Gellert-Kristensen H, Ahlberg G, et al. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis. Nat Genet. 2024;56(5):827\u201337.","journal-title":"Nat Genet"},{"key":"4888_CR81","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/s41467-020-20870-1","volume":"12","author":"VL Chen","year":"2021","unstructured":"Chen VL, Du X, Chen Y, Kuppa A, Handelman SK, Vohnoutka RB, et al. Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology. Nat Commun. 2021;12:816.","journal-title":"Nat Commun"},{"issue":"6","key":"4888_CR82","doi-asserted-by":"publisher","first-page":"428","DOI":"10.3390\/cells14060428","volume":"14","author":"T Nakamura","year":"2025","unstructured":"Nakamura T, Masuda A, Nakano D, Amano K, Sano T, Nakano M, et al. Pathogenic Mechanisms of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Associated Hepatocellular Carcinoma. Cells. 2025;14(6):428.","journal-title":"Cells"},{"issue":"10","key":"4888_CR83","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1038\/s41423-025-01307-5","volume":"22","author":"Y He","year":"2025","unstructured":"He Y, Chen Y, Qian S, van Der Merwe S, Dhar D, Brenner DA, et al. Immunopathogenic mechanisms and immunoregulatory therapies in MASLD. Cell Mol Immunol. 2025;22(10):1159\u201377.","journal-title":"Cell Mol Immunol"},{"issue":"4","key":"4888_CR84","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1161\/01.ATV.0000013904.40673.CC","volume":"22","author":"H Kato","year":"2002","unstructured":"Kato H. Regulation of Functions of Vascular Wall Cells by Tissue Factor Pathway Inhibitor. Arterioscler Thromb Vasc Biol. 2002;22(4):539\u201348.","journal-title":"Arterioscler Thromb Vasc Biol"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-026-04888-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-026-04888-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-026-04888-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:01:53Z","timestamp":1786626113000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12916-026-04888-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4888"],"URL":"https:\/\/doi.org\/10.1186\/s12916-026-04888-8","relation":{},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,26]]},"assertion":[{"value":"20 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was conducted under UK Biobank application number 104086, which has ethical approval from the UK National Health Service\u2019s National Research Ethics Service (reference 11\/NW\/0382).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors have read and understood the journal\u2019s policy on disclosing conflicts of interest, and declare that they have none to report, except for the following: Jie Zheng and Yangbo Sun are current editorial board members of BMC Medicine. The authors have no other conflicts of interest to declare.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"441"}}