Advisor(s)
Girish Melkani
Committee Member(s)
Amy Amara
Karen Gamble
Louis Dell'Italia
Vivek Nanda
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pathology
Date of Award
9-9-2024
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide and its in- cidence remains on the rise globally. In addition to other factors, CVD is associated with insomnia, which is the most common sleep disorder. It is defined as the persistent diffi- culty in initiating and/or maintaining sleep. Insomnia symptoms were found to double the risk of incident CVD. However, the specific shared causal pathways remain poorly un- derstood, making it difficult to identify new therapeutic targets that ameliorate insomnia- related CVD risks. Recently, genome-wide association studies (GWAS) identified genet- ic loci significantly associated with insomnia symptoms. Here, we identify genes near these loci that are essential for cardiac and/or sleep physiology and characterize potential mechanisms that underly the connection between CVD and insomnia. We first dissect the role of four genes near a single pleiotropic GWAS locus, related to both diseases, and report novel genes that are involved in sleep and cardiac physiology. In particular, we identify one gene, ATPSynC (ATP5G1), to be involved in both, sleep regulation and car- diac function, cell-autonomously; Imp (IGF2BP1) to be involved only in sleep physiolo- gy cell-autonomously and affect cardiac function non-cell-autonomously through sleep dysfunction; and Lsn (SNF8), to be involved only in cardiac function cell-autonomously and affect sleep fragmentation non-cell-autonomously through cardiac dysfunction. We also report disruptions in ATP Synthase and the ESCRT pathway linked with ATPSynC and Lsn, respectively, as potential underlying mechanisms involved in sleep and/or cardi- ac physiology. Additionally, through a candidate-based approach, we perform a genetic screen for 20 fly orthologs corresponding to 17 candidate human genes near insomnia- related loci and identify genes that are essential for cardiac and sleep physiology cell- autonomously and/or non-cell-autonomously. We also report a relationship between longer sleep duration and increased heart rate, demonstrating a link between sleep and cardiac dysfunction. In summary, our study unveils novel genetic candidates and poten- tial mechanisms connecting CVD and sleep disorders, offering insights into promising therapeutic targets to prevent or alleviate both conditions.
ProQuest ID
Recommended Citation
Abou Daya, Farah, "Identifying Links Between Cardiovascular Disease And Insomnia Using Human Genetics And Drosophila Models" (2024). All ETDs from UAB. 7585.
https://digitalcommons.library.uab.edu/etd-collection/7585
