{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T21:55:00Z","timestamp":1774130100920,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015339","name":"ACCP Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Second\u2010generation antipsychotic (SGA) medications are frequently prescribed for mental health conditions; however, they are associated with an increased risk of metabolic syndrome (MetS). We aimed to identify genetic associations of SGA\u2010associated MetS (SGA\u2013MetS) using genome\u2010wide approaches within the UK Biobank. We also set out to evaluate if genetically predicted obesity is associated with an increased risk of SGA\u2013MetS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We defined SGA\u2013MetS based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria using cross\u2010sectional data from 1318 UK Biobank participants who reported being on an SGA medication. An SGA\u2013MetS case was defined as meeting three or more of the five NCEP\u2010ATP III criteria. We performed a genome\u2010wide association study (GWAS) and gene\u2010based analysis to identify significant variants and gene associations. We computed the polygenic risk score (PGS) for body mass index (BMI) using 2,100,302 variants validated for obesity and metabolic traits from imputed single\u2010nucleotide polymorphism (SNP) data. We tested the association of PGS\u2013BMI with SGA\u2013MetS using logistic regression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GWAS identified suggestive associations (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20091\u2009\u00d7\u200910\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) on chromosome 15. The variant rs12914956 in\n                      <jats:italic>CHD2<\/jats:italic>\n                      was associated with increased risk of SGA (odds ratio (OR)\u2009=\u20091.73, 95% confidence interval (CI) =\u20091.4\u20132.4,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20093.6\u2009\u00d7\u200910\n                      <jats:sup>\u22127<\/jats:sup>\n                      ). The gene\u2010based analysis identified significant gene associations with\n                      <jats:italic>RBFOX1<\/jats:italic>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20094.85\u2009\u00d7\u200910\n                      <jats:sup>\u22127<\/jats:sup>\n                      ),\n                      <jats:italic>PTPRD<\/jats:italic>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20097.6\u2009\u00d7\u200910\n                      <jats:sup>\u22127<\/jats:sup>\n                      ),\n                      <jats:italic>CSMD1<\/jats:italic>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20092.2\u2009\u00d7\u200910\n                      <jats:sup>\u22126<\/jats:sup>\n                      ), and\n                      <jats:italic>CHD2<\/jats:italic>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20091.3\u2009\u00d7\u200910\n                      <jats:sup>\u22126<\/jats:sup>\n                      ). The PGS\u2013BMI (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.23,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20096.8\u2009\u00d7\u200910\n                      <jats:sup>\u22125<\/jats:sup>\n                      ), was associated with increased MetS in a model adjusted for age, sex, physical activity, alcohol consumption, antidepressant medications, schizophrenia diagnosis, and principal components of ancestry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Using a gene\u2010based analysis, we identified significant gene associations with SGA\u2013MetS that have been previously associated with obesity and metabolic traits. The PGS\u2013BMI was associated with MetS, suggesting that a genetic predisposition to a higher BMI may increase the risk of SGA\u2013MetS. Future research should replicate the findings in a larger dataset with more diverse populations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/phar.70041","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T12:45:31Z","timestamp":1754397931000},"page":"476-485","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genome\u2010wide associations with metabolic syndrome among\n                    <scp>UK<\/scp>\n                    Biobank participants reporting use of second\u2010generation antipsychotics"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-3773","authenticated-orcid":false,"given":"Nihal El","family":"Rouby","sequence":"first","affiliation":[{"name":"Division of Pharmacy Practice and Administrative Sciences, James L. Winkle College of Pharmacy University of Cincinnati  Cincinnati Ohio USA"},{"name":"St. Elizabeth HealthCare  Edgewood Kentucky USA"},{"name":"Department of Psychiatry &amp; Behavioral Neuroscience, College of Medicine University of Cincinnati  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aniwaa","family":"Owusu\u2010Obeng","sequence":"additional","affiliation":[{"name":"The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Preuss","sequence":"additional","affiliation":[{"name":"The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Lee","sequence":"additional","affiliation":[{"name":"The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjian","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics VUMC  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Lape","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bahram","family":"Namjou\u2010Khales","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Center for Autoimmune Genomics and Etiology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah C.","family":"Kottyan","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati  Cincinnati Ohio USA"},{"name":"Center for Autoimmune Genomics and Etiology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara L.","family":"Van Driest","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Vanderbilt University Medical Center (VUMC)  Nashville Tennessee USA"},{"name":"All of Us Research Program National Institutes of Health  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan D.","family":"Mosley","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics VUMC  Nashville Tennessee USA"},{"name":"Department of Medicine VUMC  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa P.","family":"DelBello","sequence":"additional","affiliation":[{"name":"Department of Psychiatry &amp; 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