{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:57:07Z","timestamp":1790805427540,"version":"4.1.0"},"reference-count":40,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed \u03b2-cell, proinsulin, obesity, lipodystrophy, and liver\/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver\/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver\/lipid cluster pPS was also significantly associated with reduced renal function. The liver\/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc21-1395","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T15:25:04Z","timestamp":1643297104000},"page":"674-683","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":69,"title":["Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts"],"prefix":"10.2337","volume":"45","author":[{"given":"Daniel","family":"DiCorpo","sequence":"first","affiliation":[{"name":"1Department of Biostatistics, Boston University School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"LeClair","sequence":"additional","affiliation":[{"name":"1Department of Biostatistics, Boston University School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne B.","family":"Cole","sequence":"additional","affiliation":[{"name":"2Programs in Metabolism and Medical & Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA"},{"name":"3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"4Division of Endocrinology, Boston Children\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"Sarnowski","sequence":"additional","affiliation":[{"name":"1Department of Biostatistics, Boston University School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-9445","authenticated-orcid":false,"given":"Fariba","family":"Ahmadizar","sequence":"additional","affiliation":[{"name":"5Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"name":"6Julius Global Health, University Utrecht Medical Center, Utrecht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence F.","family":"Bielak","sequence":"additional","affiliation":[{"name":"7Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"Blokstra","sequence":"additional","affiliation":[{"name":"8National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin P.","family":"Bottinger","sequence":"additional","affiliation":[{"name":"9Hasso Plattner Institute Digital Health, Potsdam, Germany"},{"name":"10Mount Sinai Health System, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layal","family":"Chaker","sequence":"additional","affiliation":[{"name":"5Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands"},{"name":"11Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, Rotterdam, the Netherlands"},{"name":"12Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yii-Der I.","family":"Chen","sequence":"additional","affiliation":[{"name":"13The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Chen","sequence":"additional","affiliation":[{"name":"14Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"de Vries","sequence":"additional","affiliation":[{"name":"15Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq","family":"Faquih","sequence":"additional","affiliation":[{"name":"16Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Ghanbari","sequence":"additional","affiliation":[{"name":"5Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valborg","family":"Gudmundsdottir","sequence":"additional","affiliation":[{"name":"17Icelandic Heart Association, Kopavogur, Iceland"},{"name":"18Faculty of Medicine, University of Iceland, Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqing","family":"Guo","sequence":"additional","affiliation":[{"name":"13The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie R.","family":"Hasbani","sequence":"additional","affiliation":[{"name":"15Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorina","family":"Ibi","sequence":"additional","affiliation":[{"name":"8National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands"},{"name":"19Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Arfan","family":"Ikram","sequence":"additional","affiliation":[{"name":"5Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5976-6519","authenticated-orcid":false,"given":"Maryam","family":"Kavousi","sequence":"additional","affiliation":[{"name":"5Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hampton L.","family":"Leonard","sequence":"additional","affiliation":[{"name":"20Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD"},{"name":"21Data Tecnica International, Glen Echo, MD"},{"name":"22Center for Alzheimer\u2019s and Related Dementias, National Institutes of Health, Bethesda, 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