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Here we sought to exploit this and identify new rare, protein-coding variants associated with metabolic health in WGS data (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009708,956) from the UK Biobank and All of Us studies. Identified genes highlight new biological mechanisms, including protein-truncating variants (PTVs) in the DNA double-strand break repair gene\n                    <jats:italic>RIF1<\/jats:italic>\n                    that have a substantial effect on body mass index (2.66\u2009kg\u2009m\n                    <jats:sup>\u2212<\/jats:sup>\n                    <jats:sup>2<\/jats:sup>\n                    , s.e. 0.43,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20093.7\u2009\u00d7\u200910\n                    <jats:sup>\u221210<\/jats:sup>\n                    ).\n                    <jats:italic>UBR3<\/jats:italic>\n                    is an intriguing example where PTVs independently increase body mass index and type 2 diabetes risk. Furthermore, PTVs in\n                    <jats:italic>IRS2<\/jats:italic>\n                    have a substantial effect on type 2 diabetes (odds ratio 6.4 (3.7\u201311.3),\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20099.9\u2009\u00d7\u200910\n                    <jats:sup>\u221214<\/jats:sup>\n                    , 34% case prevalence among carriers) and were also associated with chronic kidney disease independent of diabetes status, suggesting an important role for IRS2 in maintaining renal health. Our study demonstrates that large-scale WGS provides new mechanistic insights into human metabolic phenotypes through improved capture of coding sequences.\n                  <\/jats:p>","DOI":"10.1038\/s41588-025-02364-2","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T09:03:38Z","timestamp":1760087018000},"page":"2436-2444","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Population-scale gene-based analysis of whole-genome sequencing provides insights into metabolic health"],"prefix":"10.1038","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-0219","authenticated-orcid":false,"given":"Yajie","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2092-4350","authenticated-orcid":false,"given":"Sam","family":"Lockhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8379-5480","authenticated-orcid":false,"given":"Jimmy","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-0106","authenticated-orcid":false,"given":"Xihao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3490-007X","authenticated-orcid":false,"given":"Adrian","family":"Cortes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-1533","authenticated-orcid":false,"given":"Eugene J.","family":"Gardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-664X","authenticated-orcid":false,"given":"Katherine A.","family":"Kentistou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Ca\u00f1adas-Garre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3145-5357","authenticated-orcid":false,"given":"Laurie","family":"Fabian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7141-9189","authenticated-orcid":false,"given":"Nicholas","family":"Timpson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-4882","authenticated-orcid":false,"given":"Yancy","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Davitte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7857-7032","authenticated-orcid":false,"given":"David B.","family":"Savage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Buser-Doepner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken K.","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6423-0444","authenticated-orcid":false,"given":"Haoyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-3016","authenticated-orcid":false,"given":"Robert","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2199-4449","authenticated-orcid":false,"given":"Stephen","family":"O\u2019Rahilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-3771","authenticated-orcid":false,"given":"John R. 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