{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:02:45Z","timestamp":1786122165179,"version":"build-2736575974"},"reference-count":65,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005047","name":"Natural Science Foundation of Liaoning Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012131","name":"Department of Science and Technology of Liaoning Province","doi-asserted-by":"publisher","award":["2022JH2\/101300086"],"award-info":[{"award-number":["2022JH2\/101300086"]}],"id":[{"id":"10.13039\/501100012131","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Observational studies have shown that obesity is associated with an increased risk of atrial fibrillation (AF), but the underlying genetic mechanisms and direction of causality remain unclear. This study aims to systematically investigate the genetic associations, direction of causality and key pleiotropic genes linking obesity and AF by integrating large\u2010scale genome\u2010wide association study (GWAS) data and employing various genetic methods.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study utilised pooled GWAS data on obesity (FinnGen R12) and AF (a large\u2010scale GWAS meta\u2010analysis). First, linkage disequilibrium score regression (LDSC) and high\u2010definition likelihood inference (HDL) were employed to assess heritability and genetic correlation, while bidirectional Mendelian randomisation (MR) was used to infer the direction of causality. Secondly, multi\u2010trait analysis of GWAS (MTAG) was applied to the AF GWAS by integrating the obesity dataset to generate an enhanced MTAG\u2010AF dataset. Independent genetic loci were identified using functional mapping and annotation (FUMA) and GCTA conditional and joint analysis (GCTA\u2010COJO) and gene\u2010based association analyses were conducted using multi\u2010marker analysis of genomic annotation (MAGMA) and GCTA\u2010fast set\u2010based association test (GCTA\u2010fastBAT). Subsequently, tissue\u2010specific enrichment analysis using LDSC applied to specifically expressed genes (LDSC\u2010SEG), transcriptome\u2010wide association studies (TWAS) and summary\u2010data\u2010based Mendelian randomisation (SMR) were utilised to investigate the tissue\u2010specific expression of pleiotropic genes. Finally, the causal relationships between key pleiotropic genes and traits were assessed using bidirectional gene\u2010trait MR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both LDSC (rg\u2009=\u20090.2285, SE\u2009=\u20090.0257,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20097.00\u2009\u00d7\u200910\n                      <jats:sup>\u221219<\/jats:sup>\n                      ) and HDL (rg\u2009=\u20090.2885, SE\u2009=\u20090.0418,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20094.83\u2009\u00d7\u200910\n                      <jats:sup>\u221212<\/jats:sup>\n                      ) analyses confirmed a significant genetic correlation between obesity and AF. Bidirectional MR analysis revealed that obesity had a significant positive causal effect on AF (IVW: 1.160, 95% CI: 1.115\u20131.208,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20093.14\u2009\u00d7\u200910\n                      <jats:sup>\u221213<\/jats:sup>\n                      ), while no evidence of reverse causality was found (IVW: OR\u2009=\u20091.004,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.810). A total of 216 overlapping genes from FUMA and GCTA\u2010COJO and 240 shared pleiotropic genes from gene\u2010based analyses were identified, with 62 pleiotropic genes further obtained through intersection analysis. These pleiotropic genes were primarily enriched in transcriptional regulation, pathways related to myocardial action potentials and the PI3K\/AKT signalling pathway. NFATC2IP, NUCKS1 and PCCB were found to exhibit both tissue\u2010specific expression and genetic regulatory associations in adipose and cardiac tissues. Genetically predicted higher expression of NFATC2IP, NUCKS1 and PCCB was associated with increased AF risk. Higher NFATC2IP and NUCKS1 expression also increased obesity risk. Reverse MR revealed that obesity upregulated NFATC2IP expression and AF upregulated PCCB expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides genetic evidence supporting a shared genetic basis and a likely unidirectional causal relationship from obesity to AF. NFATC2IP, NUCKS1 and PCCB are identified as key pleiotropic genes, offering new genetic insights and potential therapeutic targets for obesity\u2010related AF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71016","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:40:53Z","timestamp":1781667653000},"page":"8113-8127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Genomic and Transcriptomic Analysis Reveals the Genetic Basis and Causal Association Between Obesity and Atrial Fibrillation"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0535-4583","authenticated-orcid":false,"given":"Xize","family":"Wu","sequence":"first","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine  Shenyang 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