{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:42:33Z","timestamp":1793148153803,"version":"4.5.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,1,22]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We defined all-cause HF among 488\u2009010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30\u2009201).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (\n              <jats:italic>P<\/jats:italic>\n              &lt;1\u00d710\n              <jats:sup>\u20136<\/jats:sup>\n              ), the majority linked to upstream HF risk factors, ie, coronary artery disease (\n              <jats:italic>CDKN2B-AS1<\/jats:italic>\n              and\n              <jats:italic>MAP3K7CL<\/jats:italic>\n              ) and atrial fibrillation (\n              <jats:italic>PITX2<\/jats:italic>\n              ). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (\n              <jats:italic>BAG3<\/jats:italic>\n              ,\n              <jats:italic>CLCNKA-ZBTB17<\/jats:italic>\n              ). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated\n              <jats:italic>BAG3<\/jats:italic>\n              as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03;\n              <jats:italic>P<\/jats:italic>\n              =3.62\u00d710\n              <jats:sup>\u20135<\/jats:sup>\n              ).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.035774","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T13:44:06Z","timestamp":1547732646000},"page":"489-501","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":139,"title":["Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery"],"prefix":"10.1161","volume":"139","author":[{"given":"Krishna G.","family":"Aragam","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine (K.G.A., M.E.H., S.K.), Massachusetts General Hospital, Boston."},{"name":"Cardiology Division and Cardiovascular Research Center (K.G.A., G.M., L.-C.W., M.E.L., C.N.-C., P.T.E., S.K., S.A.L.), Massachusetts General Hospital, Boston."},{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (K.G.A., M.C., S.H.C., M.E.H., L.-C.W., J.G.S., C.N.-C., P.T.E., S.K., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Chaffin","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (K.G.A., M.C., S.H.C., M.E.H., L.-C.W., J.G.S., C.N.-C., P.T.E., S.K., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca T.","family":"Levinson","sequence":"additional","affiliation":[{"name":"Department of Medicine and Division of Cardiovascular Medicine (R.T.L., M.B.S., D.M.R., Q.S.W.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"McDermott","sequence":"additional","affiliation":[{"name":"Cardiology Division and Cardiovascular Research Center (K.G.A., G.M., L.-C.W., M.E.L., C.N.-C., P.T.E., S.K., S.A.L.), Massachusetts General Hospital, Boston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hoan","family":"Choi","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (K.G.A., M.C., S.H.C., M.E.H., L.-C.W., J.G.S., C.N.-C., P.T.E., S.K., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Benjamin","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"Department of Medicine and Division of Cardiovascular Medicine (R.T.L., M.B.S., D.M.R., Q.S.W.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Haas","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine (K.G.A., M.E.H., S.K.), Massachusetts General Hospital, Boston."},{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (K.G.A., M.C., S.H.C., M.E.H., L.-C.W., J.G.S., C.N.-C., P.T.E., S.K., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Chen","family":"Weng","sequence":"additional","affiliation":[{"name":"Cardiology Division and Cardiovascular Research Center (K.G.A., G.M., L.-C.W., M.E.L., C.N.-C., P.T.E., S.K., S.A.L.), Massachusetts General Hospital, Boston."},{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (K.G.A., M.C., S.H.C., M.E.H., L.-C.W., J.G.S., C.N.-C., P.T.E., S.K., S.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Cardiology Division and Cardiovascular Research Center (K.G.A., G.M., L.-C.W., M.E.L., C.N.-C., P.T.E., S.K., S.A.L.), Massachusetts General Hospital, Boston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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