{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:29:59Z","timestamp":1791898199203,"version":"4.3.4"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,5,17]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We performed a genome-wide association study of the QTc in 84\u2009630 UK Biobank participants and created a polygenic risk score (PRS). Among 26\u2009976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1\u2009110\u2009494 common variants was significantly associated with the QTc in TOPMed (\u0394QTc\n                      <jats:sub>\/decile of PRS<\/jats:sub>\n                      =1.4 ms [95% CI, 1.3 to 1.5];\n                      <jats:italic>P<\/jats:italic>\n                      =1.1\u00d710\n                      <jats:sup>-196<\/jats:sup>\n                      ). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (\u0394QTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc&gt;480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.121.057261","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T13:00:39Z","timestamp":1649336439000},"page":"1524-1533","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Monogenic and Polygenic Contributions to QTc Prolongation in the Population"],"prefix":"10.1161","volume":"145","author":[{"given":"Victor","family":"Nauffal","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine (V.N.), Brigham and Women\u2019s Hospital, Boston, MA."},{"name":"Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3245-304X","authenticated-orcid":true,"given":"Valerie N.","family":"Morrill","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":true,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA."},{"name":"Department of Experimental Cardiology, Amsterdam University Medical Centers, The Netherlands (S.J.J.)."},{"name":"Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (N.G., S.J.J., S.H.C., L.C.W., J.L.H., C.A.T., H.L.R., P.T.E., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hoan","family":"Choi","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA."},{"name":"Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (N.G., S.J.J., S.H.C., L.C.W., J.L.H., C.A.T., H.L.R., P.T.E., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia W.","family":"Hall","sequence":"additional","affiliation":[{"name":"Gene Regulation Observatory (A.W.H.), Broad Institute, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Chen","family":"Weng","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA."},{"name":"Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (N.G., S.J.J., S.H.C., L.C.W., J.L.H., C.A.T., H.L.R., P.T.E., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1454-3650","authenticated-orcid":true,"given":"Jennifer L.","family":"Halford","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA."},{"name":"Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (N.G., S.J.J., S.H.C., L.C.W., J.L.H., C.A.T., H.L.R., P.T.E., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6492-6716","authenticated-orcid":true,"given":"Christina","family":"Austin-Tse","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine (C.A.-T., H.L.R.), Massachusetts General Hospital, Boston."},{"name":"Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (N.G., S.J.J., S.H.C., L.C.W., J.L.H., C.A.T., H.L.R., P.T.E., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3227-4490","authenticated-orcid":true,"given":"Christopher M.","family":"Haggerty","sequence":"additional","affiliation":[{"name":"Department of Translational Data Science and Informatics, Geisinger, Danville, PA (C.M.H., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie 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