{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T00:01:00Z","timestamp":1792886460020,"version":"4.5.0"},"reference-count":101,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004785","name":"NordForsk","doi-asserted-by":"publisher","award":["90580"],"award-info":[{"award-number":["90580"]}],"id":[{"id":"10.13039\/501100004785","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012774","name":"Innovation Fund Denmark","doi-asserted-by":"publisher","award":["8114-00033B"],"award-info":[{"award-number":["8114-00033B"]}],"id":[{"id":"10.13039\/100012774","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Technology Development Fund","award":["90580"],"award-info":[{"award-number":["90580"]}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We performed a genome-wide association study of 6469 SSS cases and 1\u00a0000\u00a0187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)\/electrocardiogram variants at PITX2, ZFHX3, TTN\/CCDC141, and SCN10A and a low-frequency (MAF = 1.1\u20131.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P\u2009=\u20091.6\u2009\u00d7\u200910\u221220), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P\u2009&amp;gt;\u20090.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaa1108","type":"journal-article","created":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T17:22:50Z","timestamp":1609867370000},"page":"1959-1971","source":"Crossref","is-referenced-by-count":56,"title":["Genetic insight into sick sinus syndrome"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7475-0398","authenticated-orcid":false,"given":"Rosa B","family":"Thorolfsdottir","sequence":"first","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2429-9468","authenticated-orcid":false,"given":"Gardar","family":"Sveinbjornsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildur M","family":"Aegisdottir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5019-514X","authenticated-orcid":false,"given":"Stefania","family":"Benonisdottir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilja","family":"Stefansdottir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2069-0681","authenticated-orcid":false,"given":"Erna V","family":"Ivarsdottir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7067-9862","authenticated-orcid":false,"given":"Gisli H","family":"Halldorsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon K","family":"Sigurdsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc. , Sturlugata 8, Reykjavik 101, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2892-6131","authenticated-orcid":false,"given":"Christian","family":"Torp-Pedersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Research and Cardiology, Nordsjaelland Hospital , Dyrehavevej 29, Hiller\u00f8d 3400, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E","family":"Weeke","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital , Blegdamsvej 9, Copenhagen 2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Brunak","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3A, Copenhagen 2200, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0128-8432","authenticated-orcid":false,"given":"David","family":"Westergaard","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 3A, Copenhagen 2200, 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