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We developed an image- and CRISPR\/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[\n                    <jats:italic>acta2:GFP<\/jats:italic>\n                    ]), to visualize the beating heart\n                    <jats:italic>.<\/jats:italic>\n                    An automated analysis of repeated 30\u00a0s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5\u00a0days post-fertilization highlighted genes that influence HRV (\n                    <jats:italic>hcn4<\/jats:italic>\n                    and\n                    <jats:italic>si:dkey-65j6.2 [KIAA1755]<\/jats:italic>\n                    ); heart rate (\n                    <jats:italic>rgs6 and hcn4<\/jats:italic>\n                    ); and the risk of sinoatrial pauses and arrests (\n                    <jats:italic>hcn4<\/jats:italic>\n                    ). Exposure to 10 or 25\u00a0\u00b5M ivabradine\u2014an open channel blocker of HCNs\u2014for 24\u00a0h resulted in a dose-dependent higher HRV and lower heart rate at 5\u00a0days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (\n                    <jats:italic>RGS6<\/jats:italic>\n                    and\n                    <jats:italic>HCN4<\/jats:italic>\n                    ); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (\n                    <jats:italic>KIAA1755<\/jats:italic>\n                    ).\n                  <\/jats:p>","DOI":"10.1038\/s41598-020-68567-1","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T06:04:22Z","timestamp":1594879462000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR\/Cas9-based approach"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-4027","authenticated-orcid":false,"given":"Benedikt","family":"von der Heyde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Emmanouilidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Mazzaferro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Vicenzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"H\u00f6ijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Klingstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitaf","family":"Jumaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Dethlefsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1949-2298","authenticated-orcid":false,"given":"Harold","family":"Snieder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6022-2666","authenticated-orcid":false,"given":"Eco","family":"de Geus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6085-6749","authenticated-orcid":false,"given":"Adam","family":"Ameur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2256-6972","authenticated-orcid":false,"given":"Erik","family":"Ingelsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Allalou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Brooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8081-428X","authenticated-orcid":false,"given":"Marcel","family":"den Hoed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"key":"68567_CR1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.ijcard.2009.09.543","volume":"141","author":"JF Thayer","year":"2010","unstructured":"Thayer, J. 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