Identifying novel links between cardiovascular disease and insomnia byDrosophilamodeling of genes from a pleiotropic GWAS locus

Abstract

AbstractBackgroundInsomnia symptoms have been associated with CVD, doubling the risk of incident CVD, but specific shared pathways remain poorly understood. Recently, genome-wide association studies (GWAS) identified genetic loci significantly associated with insomnia symptoms, including one locus that was previously associated with CVD in an independent GWAS.MethodsTo evaluate the cell-autonomous role of genes near the CVD- and insomnia-related locus, we usedDrosophila melanogastermodels to perform tissue-specific RNAi knockdown of these genes in the heart and neurons. We also performed suppression of these genes in the heart or neurons, and assessed sleep or cardiac function, respectively, to identify non-cell-autonomous mechanisms.ResultsOur results show that neuronal and cardiac-specific RNAi knockdown of four genes conserved inDrosophila,Lsn, ATPSynC, Bruce, andImp, contributes to compromised sleep and cardiac performance, respectively. Cardiac-specific knockdown ofLsnled to significant cardiac dilation and reduced cardiac performance. Knockdown ofATPSynCled to significantly reduced cardiac performance without dilations. Furthermore,LsnandATPSynC-suppressed hearts showed disruption in the actin-containing myofibrillar organization and led to a significantly shortened lifespan. Suppression ofLsnincreased pericardin deposition, indicative of a fibrotic phenotype. Neuronal-specific knockdown ofATPSynC, Imp, and Lsnled to compromised sleep. Moreover, the knockdown ofImpin the brain led to a significantly compromised cardiac function characterized by decreased systolic and diastolic intervals and fractional shortening in a non-cell autonomous manner. Furthermore, the knockdown ofBruce,ATPSynC,andLsnin the heart led to compromised sleep characterized by decreased activity and daytime activity and increased bin number in a non-cell autonomous manner.ConclusionsOur study provides novel insights into genetic mechanisms linking CVD and insomnia, highlighting the importance of these four conserved genes in the development and association of both diseases.