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Genome-wide association studies identified a genetic locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1 and GIP) linked to insomnia and CVD. We used Drosophila models to perform tissue-specific RNA interference knockdowns of four conserved orthologs (ATPsynC, lsn, Bruce and Imp) in neurons and the heart. Neuronal-specific knockdown of ATPsynC, Imp and lsn impaired sleep quantity and quality. In contrast, cardiac knockdown of ATPsynC and lsn reduced cardiac function and lifespan, with lsn knockdown also causing cardiac dilation and myofibrillar disorganization. Cross-tissue effects were evident: neuronal Imp knockdown compromised cardiac function, whereas cardiac ATPsynC and lsn knockdown increased sleep fragmentation and inflammation (marked by Upd3 elevation in the heart or head). Overexpression of Upd3 in neurons impaired cardiac function, and its overexpression in the heart disrupted sleep. Our findings reveal conserved genes mediating tissue-specific and cross-tissue interactions between sleep and cardiac function, providing novel insights into the genetic mechanisms linking insomnia and CVD through inflammation.<\/jats:p>","DOI":"10.1242\/dmm.052139","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T07:32:52Z","timestamp":1743665572000},"source":"Crossref","is-referenced-by-count":14,"title":["Identifying links between cardiovascular disease and insomnia by modeling genes from a pleiotropic locus"],"prefix":"10.1242","volume":"18","author":[{"given":"Farah","family":"Abou Daya","sequence":"first","affiliation":[{"name":"Heersink School of Medicine, The University of Alabama at Birmingham 1 Department of Pathology, Division of Molecular and Cellular Pathology , , Birmingham, AL 35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torrey","family":"Mandigo","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 ,","place":["USA"]},{"name":"Massachusetts General Hospital, Harvard Medical School 3 Department of Neurology , , Boston, MA 02114 ,","place":["USA"]},{"name":"Broad Institute of MIT and Harvard 4 Cancer Program , , Cambridge, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Ober","sequence":"additional","affiliation":[{"name":"Heersink School of Medicine, The University of Alabama at Birmingham 1 Department of Pathology, Division of Molecular and Cellular Pathology , , Birmingham, AL 35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dev","family":"Patel","sequence":"additional","affiliation":[{"name":"Heersink School of Medicine, The University of Alabama at Birmingham 1 Department of Pathology, Division of Molecular and Cellular Pathology , , Birmingham, AL 35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Maher","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suraj","family":"Math","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 ,","place":["USA"]},{"name":"Massachusetts General Hospital, Harvard Medical School 3 Department of Neurology , , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Tchio","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Walker","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 ,","place":["USA"]},{"name":"Massachusetts General Hospital, Harvard Medical School 3 Department of Neurology , , Boston, MA 02114 ,","place":["USA"]},{"name":"Broad Institute of MIT and Harvard 4 Cancer Program , , Cambridge, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa","family":"Saxena","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 ,","place":["USA"]},{"name":"Broad Institute of MIT and Harvard 4 Cancer Program , , Cambridge, MA 02114 ,","place":["USA"]},{"name":"Massachusetts General Hospital and Harvard Medical School 5 Department of Anesthesia, Critical Care and Pain Medicine , , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0353-4633","authenticated-orcid":false,"given":"Girish C.","family":"Melkani","sequence":"additional","affiliation":[{"name":"Heersink School of Medicine, The University of Alabama at Birmingham 1 Department of Pathology, Division of Molecular and Cellular Pathology , , Birmingham, AL 35294 ,","place":["USA"]},{"name":"UAB Nathan Shock Center 6 , Birmingham, AL 35294 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"2025050604055486500_DMM052139C1","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1038\/s41588-022-01233-6","article-title":"Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants","volume":"54","author":"Aragam","year":"2022","journal-title":"Nat. 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