{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T05:44:48Z","timestamp":1793771088847,"version":"4.6.1"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200936,394), six replicated in four independent cohorts (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093,903). Next, we generated two partitioned polygenic risk scores based on the presence of lipoprotein retention in the liver. The two polygenic risk scores suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease. These findings shed light on the heterogeneity of MASLD and have the potential to improve the prediction of clinical trajectories and inform precision medicine approaches.\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03284-0","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T05:03:49Z","timestamp":1733720629000},"page":"3614-3623","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":157,"title":["Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7139-4738","authenticated-orcid":false,"given":"Oveis","family":"Jamialahmadi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"De Vincentis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1720-4355","authenticated-orcid":false,"given":"Federica","family":"Tavaglione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2430-5883","authenticated-orcid":false,"given":"Francesco","family":"Malvestiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifang","family":"Li-Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1126-3071","authenticated-orcid":false,"given":"Rosellina M.","family":"Mancina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-5028","authenticated-orcid":false,"given":"Marcus","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyla","family":"Gelev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Maurotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umberto","family":"Vespasiani-Gentilucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2558-7496","authenticated-orcid":false,"given":"Frits Richard","family":"Rosendaal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-2290","authenticated-orcid":false,"given":"Julia","family":"Kozlitina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6423-8056","authenticated-orcid":false,"given":"P\u00e4ivi","family":"Pajukanta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Pattou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8909-0345","authenticated-orcid":false,"given":"Luca","family":"Valenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9168-4898","authenticated-orcid":false,"given":"Stefano","family":"Romeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"3284_CR1","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1056\/NEJMoa2029349","volume":"385","author":"AJ Sanyal","year":"2021","unstructured":"Sanyal, A. J. et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N. Engl. J. Med. 385, 1559\u20131569 (2021).","journal-title":"N. Engl. J. Med."},{"key":"3284_CR2","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1002\/hep.30223","volume":"69","author":"R Pais","year":"2019","unstructured":"Pais, R., Redheuil, A., Cluzel, P., Ratziu, V. & Giral, P. Relationship among fatty liver, specific and multiple-site atherosclerosis, and 10-year Framingham score. Hepatology 69, 1453\u20131463 (2019).","journal-title":"Hepatology"},{"key":"3284_CR3","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/nrgastro.2013.41","volume":"10","author":"QM Anstee","year":"2013","unstructured":"Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330\u2013344 (2013).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"3284_CR4","doi-asserted-by":"publisher","first-page":"2462","DOI":"10.1016\/j.cgh.2021.09.021","volume":"20","author":"JZK Toh","year":"2022","unstructured":"Toh, J. Z. K. et al. A meta-analysis on the global prevalence, risk factors and screening of coronary heart disease in nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 20, 2462\u20132473.e2410 (2022).","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"3284_CR5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cmet.2019.12.002","volume":"31","author":"S Romeo","year":"2020","unstructured":"Romeo, S., Sanyal, A. & Valenti, L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 31, 35\u201345 (2020).","journal-title":"Cell Metab."},{"key":"3284_CR6","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1111\/apt.17477","volume":"57","author":"A Mantovani","year":"2023","unstructured":"Mantovani, A. et al. Adverse effect of PNPLA3 p.I148M genetic variant on kidney function in middle-aged individuals with metabolic dysfunction. Aliment Pharm. Ther. 57, 1093\u20131102 (2023).","journal-title":"Aliment Pharm. Ther."},{"key":"3284_CR7","doi-asserted-by":"publisher","first-page":"386","DOI":"10.21037\/hbsn-22-421","volume":"12","author":"DQ Sun","year":"2023","unstructured":"Sun, D. Q. et al. An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease. Hepatobiliary Surg. Nutr. 12, 386\u2013403 (2023).","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"3284_CR8","doi-asserted-by":"publisher","unstructured":"Chen, Y. et al. Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. Nat. Genet. https:\/\/doi.org\/10.1038\/s41588-023-01497-6 (2023).","DOI":"10.1038\/s41588-023-01497-6"},{"key":"3284_CR9","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/s41588-022-01078-z","volume":"54","author":"M Vujkovic","year":"2022","unstructured":"Vujkovic, M. 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. 54, 761\u2013771 (2022).","journal-title":"Nat. Genet."},{"key":"3284_CR10","doi-asserted-by":"publisher","first-page":"e1008629","DOI":"10.1371\/journal.pgen.1008629","volume":"16","author":"CA Emdin","year":"2020","unstructured":"Emdin, C. A. et al. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease. PLoS Genet. 16, e1008629 (2020).","journal-title":"PLoS Genet."},{"key":"3284_CR11","first-page":"100056","volume":"3","author":"Z Miao","year":"2022","unstructured":"Miao, Z. et al. Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease. HGG Adv. 3, 100056 (2022).","journal-title":"HGG Adv."},{"key":"3284_CR12","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1053\/j.gastro.2020.12.023","volume":"160","author":"O Jamialahmadi","year":"2021","unstructured":"Jamialahmadi, O. et al. Exome-wide association study on alanine aminotransferase identifies sequence variants in the GPAM and APOE associated with fatty liver disease. Gastroenterology 160, 1634\u20131646.e1637 (2021).","journal-title":"Gastroenterology"},{"key":"3284_CR13","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1038\/ng.257","volume":"40","author":"S Romeo","year":"2008","unstructured":"Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461\u20131465 (2008).","journal-title":"Nat. Genet."},{"key":"3284_CR14","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/ijo.2009.216","volume":"34","author":"S Romeo","year":"2010","unstructured":"Romeo, S. et al. Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J. Obes. 34, 190\u2013194 (2010).","journal-title":"Int J. Obes."},{"key":"3284_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30931-2","volume":"13","author":"S Agrawal","year":"2022","unstructured":"Agrawal, S. et al. Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots. Nat. Commun. 13, 3771 (2022).","journal-title":"Nat. Commun."},{"key":"3284_CR16","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":"3284_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8","volume":"4","author":"CC Chang","year":"2015","unstructured":"Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4, 7 (2015).","journal-title":"GigaScience"},{"key":"3284_CR18","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/ng.2213","volume":"44","author":"J Yang","year":"2012","unstructured":"Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369\u2013375 (2012).","journal-title":"Nat. Genet."},{"key":"3284_CR19","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41588-018-0047-6","volume":"50","author":"M Kanai","year":"2018","unstructured":"Kanai, M. et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390\u2013400 (2018).","journal-title":"Nat. Genet."},{"key":"3284_CR20","doi-asserted-by":"publisher","first-page":"3555","DOI":"10.1093\/bioinformatics\/btv402","volume":"31","author":"MJ Machiela","year":"2015","unstructured":"Machiela, M. J. & Chanock, S. J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555\u20133557 (2015).","journal-title":"Bioinformatics"},{"key":"3284_CR21","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1111\/joim.12719","volume":"283","author":"P Dongiovanni","year":"2018","unstructured":"Dongiovanni, P. et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J. Intern. Med. 283, 356\u2013370 (2018).","journal-title":"J. Intern. Med."},{"key":"3284_CR22","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1038\/ng.3855","volume":"49","author":"S Stender","year":"2017","unstructured":"Stender, S. et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 49, 842\u2013847 (2017).","journal-title":"Nat. Genet."},{"key":"3284_CR23","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1128\/MCB.01344-13","volume":"34","author":"MS Madsen","year":"2014","unstructured":"Madsen, M. S., Siersb\u00e6k, R., Boergesen, M., Nielsen, R. & Mandrup, S. Peroxisome proliferator-activated receptor \u03b3 and C\/EBP\u03b1 synergistically activate key metabolic adipocyte genes by assisted loading. Mol. Cell. Biol. 34, 939\u2013954 (2014).","journal-title":"Mol. Cell. Biol."},{"key":"3284_CR24","doi-asserted-by":"publisher","first-page":"452061","DOI":"10.1155\/2013\/452061","volume":"2013","author":"P Dongiovanni","year":"2013","unstructured":"Dongiovanni, P. & Valenti, L. Peroxisome proliferator-activated receptor genetic polymorphisms and nonalcoholic fatty liver disease: any role in disease susceptibility? PPAR Res. 2013, 452061 (2013).","journal-title":"PPAR Res."},{"key":"3284_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-69363-7","volume":"10","author":"N Sarhangi","year":"2020","unstructured":"Sarhangi, N. et al. PPARG (Pro12Ala) genetic variant and risk of T2DM: a systematic review and meta-analysis. Sci. Rep. 10, 12764 (2020).","journal-title":"Sci. Rep."},{"key":"3284_CR26","doi-asserted-by":"publisher","first-page":"2341","DOI":"10.2337\/diabetes.51.8.2341","volume":"51","author":"M Stumvoll","year":"2002","unstructured":"Stumvoll, M. & H\u00e4ring, H. The peroxisome proliferator-activated receptor-\u03b32 Pro12Ala polymorphism. Diabetes 51, 2341\u20132347 (2002).","journal-title":"Diabetes"},{"key":"3284_CR27","doi-asserted-by":"publisher","first-page":"460190","DOI":"10.1155\/2015\/460190","volume":"2015","author":"P Dongiovanni","year":"2015","unstructured":"Dongiovanni, P., Romeo, S. & Valenti, L. Genetic factors in the pathogenesis of nonalcoholic fatty liver and steatohepatitis. BioMed. Res. Int. 2015, 460190 (2015).","journal-title":"BioMed. Res. Int."},{"key":"3284_CR28","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/ng.3714","volume":"49","author":"LA Lotta","year":"2017","unstructured":"Lotta, L. A. et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat. Genet. 49, 17\u201326 (2017).","journal-title":"Nat. Genet."},{"key":"3284_CR29","doi-asserted-by":"publisher","first-page":"207","DOI":"10.2337\/db18-0708","volume":"68","author":"Y Ji","year":"2019","unstructured":"Ji, Y. et al. Genome-wide and abdominal MRI data provide evidence that a genetically determined favorable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease and hypertension. Diabetes 68, 207\u2013219 (2019).","journal-title":"Diabetes"},{"key":"3284_CR30","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1093\/pan\/mps040","volume":"21","author":"K Imai","year":"2013","unstructured":"Imai, K. & Yamamoto, T. Identification and sensitivity analysis for multiple causal mechanisms: revisiting evidence from framing experiments. Political Anal. 21, 141\u2013171 (2013).","journal-title":"Political Anal."},{"key":"3284_CR31","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1023\/A:1026595011371","volume":"1","author":"DP MacKinnon","year":"2000","unstructured":"MacKinnon, D. P., Krull, J. L. & Lockwood, C. M. Equivalence of the mediation, confounding and suppression effect. Prev. Sci. 1, 173\u2013181 (2000).","journal-title":"Prev. Sci."},{"key":"3284_CR32","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1002\/hep.27490","volume":"61","author":"P Dongiovanni","year":"2015","unstructured":"Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506\u2013514 (2015).","journal-title":"Hepatology"},{"key":"3284_CR33","doi-asserted-by":"publisher","first-page":"489","DOI":"10.5551\/jat.RV17040","volume":"27","author":"H Tada","year":"2020","unstructured":"Tada, H., Usui, S., Sakata, K., Takamura, M. & Kawashiri, M. A. Low-density lipoprotein cholesterol level cannot be too low: considerations from clinical trials, human genetics and biology. J. Atheroscler. Thromb. 27, 489\u2013498 (2020).","journal-title":"J. Atheroscler. Thromb."},{"key":"3284_CR34","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1093\/eurheartj\/ehx662","volume":"39","author":"BK Lauridsen","year":"2018","unstructured":"Lauridsen, B. K. et al. Liver fat content, non-alcoholic fatty liver disease and ischaemic heart disease: Mendelian randomization and meta-analysis of 279013 individuals. Eur. Heart J. 39, 385\u2013393 (2018).","journal-title":"Eur. Heart J."},{"key":"3284_CR35","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1038\/s41591-024-02865-3","volume":"30","author":"K Smith","year":"2024","unstructured":"Smith, K. et al. Multi-ancestry polygenic mechanisms of type 2 diabetes. Nat. Med. 30, 1065\u20131074 (2024).","journal-title":"Nat. Med."},{"key":"3284_CR36","doi-asserted-by":"publisher","first-page":"e1002654","DOI":"10.1371\/journal.pmed.1002654","volume":"15","author":"MS Udler","year":"2018","unstructured":"Udler, M. S. et al. Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: a soft clustering analysis. PLoS Med. 15, e1002654 (2018).","journal-title":"PLoS Med."},{"key":"3284_CR37","doi-asserted-by":"publisher","first-page":"2643","DOI":"10.1038\/s41591-023-02553-8","volume":"29","author":"A Cherubini","year":"2023","unstructured":"Cherubini, A. et al. Interaction between estrogen receptor-\u03b1 and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nat. Med. 29, 2643\u20132655 (2023).","journal-title":"Nat. Med."},{"key":"3284_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47737-w","volume":"9","author":"S Prill","year":"2019","unstructured":"Prill, S. et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci. Rep. 9, 11585 (2019).","journal-title":"Sci. Rep."},{"key":"3284_CR39","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.jhep.2012.07.030","volume":"57","author":"C Pirazzi","year":"2012","unstructured":"Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276\u20131282 (2012).","journal-title":"J. Hepatol."},{"key":"3284_CR40","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/ng.2926","volume":"46","author":"OL Holmen","year":"2014","unstructured":"Holmen, O. L. et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat. Genet. 46, 345\u2013351 (2014).","journal-title":"Nat. Genet."},{"key":"3284_CR41","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1210\/er.2019-00088","volume":"40","author":"MS Udler","year":"2019","unstructured":"Udler, M. S., McCarthy, M. I., Florez, J. C. & Mahajan, A. Genetic risk scores for diabetes diagnosis and precision medicine. Endocr. Rev. 40, 1500\u20131520 (2019).","journal-title":"Endocr. Rev."},{"key":"3284_CR42","doi-asserted-by":"publisher","first-page":"100284","DOI":"10.1016\/j.jhepr.2021.100284","volume":"3","author":"C Bianco","year":"2021","unstructured":"Bianco, C., Casirati, E., Malvestiti, F. & Valenti, L. Genetic predisposition similarities between NASH and ASH:identification of new therapeutic targets. JHEP Rep. 3, 100284 (2021).","journal-title":"JHEP Rep."},{"key":"3284_CR43","doi-asserted-by":"publisher","unstructured":"Raverdy, V. et al. Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease. Nat. Med. https:\/\/doi.org\/10.1038\/s41591-024-03283-1 (2024).","DOI":"10.1038\/s41591-024-03283-1"},{"key":"3284_CR44","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":"3284_CR45","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.jhep.2020.03.032","volume":"73","author":"CA Parisinos","year":"2020","unstructured":"Parisinos, C. A. et al. Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis. J. Hepatol. 73, 241\u2013251 (2020).","journal-title":"J. Hepatol."},{"key":"3284_CR46","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1111\/liv.15556","volume":"43","author":"O Jamialahmadi","year":"2023","unstructured":"Jamialahmadi, O., Tavaglione, F., Rawshani, A., Ljungman, C. & Romeo, S. Fatty liver disease, heart rate and cardiac remodelling: evidence from the UK Biobank. Liver Int. 43, 1247\u20131255 (2023).","journal-title":"Liver Int."},{"key":"3284_CR47","doi-asserted-by":"publisher","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","volume":"47","author":"A Buniello","year":"2019","unstructured":"Buniello, A. et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005\u2013D1012 (2019).","journal-title":"Nucleic Acids Res."},{"key":"3284_CR48","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","volume":"47","author":"BK Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291\u2013295 (2015).","journal-title":"Nat. Genet."},{"key":"3284_CR49","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1038\/ng.3954","volume":"49","author":"S Gazal","year":"2017","unstructured":"Gazal, S. et al. Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection. Nat. Genet. 49, 1421\u20131427 (2017).","journal-title":"Nat. Genet."},{"key":"3284_CR50","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1101\/gr.092759.109","volume":"19","author":"M Krzywinski","year":"2009","unstructured":"Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639\u20131645 (2009).","journal-title":"Genome Res."},{"key":"3284_CR51","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1038\/s41588-020-00735-5","volume":"52","author":"O Weissbrod","year":"2020","unstructured":"Weissbrod, O. et al. Functionally informed fine-mapping and polygenic localization of complex trait heritability. Nat. Genet. 52, 1355\u20131363 (2020).","journal-title":"Nat. Genet."},{"key":"3284_CR52","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1111\/rssb.12388","volume":"82","author":"G Wang","year":"2020","unstructured":"Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. J. R. Stat. Soc. Ser. B Stat. Methodol. 82, 1273\u20131300 (2020).","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"3284_CR53","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1038\/s41588-021-00924-w","volume":"53","author":"N Kerimov","year":"2021","unstructured":"Kerimov, N. et al. A compendium of uniformly processed human gene expression and splicing quantitative trait loci. Nat. Genet. 53, 1290\u20131299 (2021).","journal-title":"Nat. Genet."},{"key":"3284_CR54","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1126\/science.aaz1776","volume":"369","author":"G Consortium","year":"2020","unstructured":"Consortium, G. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318\u20131330 (2020).","journal-title":"Science"},{"key":"3284_CR55","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1093\/bioinformatics\/btp328","volume":"25","author":"M Lawrence","year":"2009","unstructured":"Lawrence, M., Gentleman, R. & Carey, V. rtracklayer: an R package for interfacing with genome browsers. Bioinformatics 25, 1841\u20131842 (2009).","journal-title":"Bioinformatics"},{"key":"3284_CR56","doi-asserted-by":"publisher","first-page":"e1009440","DOI":"10.1371\/journal.pgen.1009440","volume":"17","author":"C Wallace","year":"2021","unstructured":"Wallace, C. A more accurate method for colocalisation analysis allowing for multiple causal variants. PLoS Genet. 17, e1009440 (2021).","journal-title":"PLoS Genet."},{"key":"3284_CR57","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5","volume":"8","author":"K Watanabe","year":"2017","unstructured":"Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).","journal-title":"Nat. Commun."},{"key":"3284_CR58","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."},{"key":"3284_CR59","doi-asserted-by":"publisher","first-page":"D1311","DOI":"10.1093\/nar\/gkaa840","volume":"49","author":"M Ghoussaini","year":"2021","unstructured":"Ghoussaini, M. et al. Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics. Nucleic Acids Res. 49, D1311\u2013D1320 (2021).","journal-title":"Nucleic Acids Res."},{"key":"3284_CR60","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1002\/cpz1.90","volume":"1","author":"Z Xie","year":"2021","unstructured":"Xie, Z. et al. Gene set knowledge discovery with Enrichr. Curr. Protoc. 1, e90 (2021).","journal-title":"Curr. Protoc."},{"key":"3284_CR61","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1007\/s10654-013-9801-3","volume":"28","author":"R de Mutsert","year":"2013","unstructured":"de Mutsert, R. et al. The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection. Eur. J. Epidemiol. 28, 513\u2013523 (2013).","journal-title":"Eur. J. Epidemiol."},{"key":"3284_CR62","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.1002\/hep4.1794","volume":"5","author":"L Valenti","year":"2021","unstructured":"Valenti, L. et al. Definition of healthy ranges for alanine aminotransferase levels: a 2021 update. Hepatol. Commun. 5, 1824\u20131832 (2021).","journal-title":"Hepatol. Commun."},{"key":"3284_CR63","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1056\/NEJMoa2020283","volume":"383","author":"D Ellinghaus","year":"2020","unstructured":"Ellinghaus, D. et al. Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med. 383, 1522\u20131534 (2020).","journal-title":"N. Engl. J. Med."},{"key":"3284_CR64","doi-asserted-by":"publisher","unstructured":"Tavaglione, F. et al. Accuracy of controlled attenuation parameter for assessing liver steatosis in individuals with morbid obesity before bariatric surgery. Liver Int. https:\/\/doi.org\/10.1111\/liv.15127 (2021).","DOI":"10.1111\/liv.15127"},{"key":"3284_CR65","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15\u201321 (2013).","journal-title":"Bioinformatics"},{"key":"3284_CR66","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","volume":"30","author":"AM Bolger","year":"2014","unstructured":"Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114\u20132120 (2014).","journal-title":"Bioinformatics"},{"key":"3284_CR67","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1186\/1471-2105-12-323","volume":"12","author":"B Li","year":"2011","unstructured":"Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform. 12, 323 (2011).","journal-title":"BMC Bioinform."},{"key":"3284_CR68","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"3284_CR69","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","volume":"28","author":"JT Leek","year":"2012","unstructured":"Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E. & Storey, J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882\u2013883 (2012).","journal-title":"Bioinformatics"},{"key":"3284_CR70","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.ajhg.2020.11.016","volume":"108","author":"AR Marderstein","year":"2021","unstructured":"Marderstein, A. R. et al. Leveraging phenotypic variability to identify genetic interactions in human phenotypes. Am. J. Hum. Genet. 108, 49\u201367 (2021).","journal-title":"Am. J. Hum. Genet"},{"key":"3284_CR71","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15107-0","volume":"11","author":"J Sulc","year":"2020","unstructured":"Sulc, J. et al. Quantification of the overall contribution of gene-environment interaction for obesity-related traits. Nat. Commun. 11, 1385 (2020).","journal-title":"Nat. Commun."},{"key":"3284_CR72","doi-asserted-by":"publisher","unstructured":"Tingley, D., Yamamoto, T., Hirose, K., Keele, L. & Imai, K. mediation: R package for causal mediation analysis. J. Stat. Softw. https:\/\/doi.org\/10.18637\/jss.v059.i05 (2014).","DOI":"10.18637\/jss.v059.i05"}],"updated-by":[{"DOI":"10.1038\/s41591-025-03503-2","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000}}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03284-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03284-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03284-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T05:07:44Z","timestamp":1740546464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03284-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":72,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["3284"],"URL":"https:\/\/doi.org\/10.1038\/s41591-024-03284-0","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3878807\/v1","asserted-by":"object"}]},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12]]},"assertion":[{"value":"19 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2025","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41591-025-03503-2","URL":"https:\/\/doi.org\/10.1038\/s41591-025-03503-2","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.R. has been consulting for AstraZeneca, GSK, Celgene Corporation, Ribo-cure AB and Pfizer in the last 5 years and received a research grant from AstraZeneca. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the paper or in the decision to publish the results. L.V. has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics, Ionis Pharmaceuticals, Boehringer Ingelheim and Resalis Therapeutics, and received unrestricted research grants from Gilead. R.L.G. is a part-time contractor for Metabolon. O.J. is a part-time consultant to Ribo-cure AB. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}