![]() Taken together, we hypothesized that there might be a shared genetic basis underlying these connections between AD and sleep disorders. Importantly, amyloid β and tau protein, which are core hallmarks of AD, can exacerbate the sleeping status sleep disorder in an AD person ( Liu et al., 2019). In animal models, sleep disturbance and increased arousal lead to increased Aβ production and decreased Aβ clearance, while chronic increased arousal promotes Aβ aggregation and deposition, thus leading to sleep disturbance ( Wang and Holtzman, 2020). Furthermore, neuropathological studies have shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep-wake cycle ( Wang and Holtzman, 2020). Emerging epidemiological studies suggest that AD is associated with a significantly increased risk of sleep disorders and vice versa ( Andrade et al., 2018 Brzecka et al., 2018 Shi et al., 2018 Sadeghmousavi et al., 2020). Growing evidence indicates that AD patients frequently have sleep disorders, implying common causes of these complex phenotypes. Identifying shared drug targets and molecular pathways can be beneficial for treating AD and sleep disorders more efficiently.Īlzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and overall cognitive decline ( McKhann et al., 2011) and is highly heritable (heritability 58–79%) ( Sims et al., 2020). Our findings provide strong evidence of shared genetics and causation between AD and sleep abnormalities and advance our understanding of the genetic overlap between them. MR showed insomnia had a causal effect on AD (OR IVW = 1.02, P IVW = 6.7 × 10 –6), and multivariate MR suggested a potential role of sleep duration and major depression in this association. The CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3, and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. Protein–protein interaction analysis identified three potential drug target genes ( APOE, MARK4, and HLA-DRA) that interacted with known FDA-approved drug target genes. Functional analysis and the TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues and highlighted the regulatory roles of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance, and positive regulation of T-cell–mediated cytotoxicity pathways. The CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross-phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD ( N = 455,258) and summary-level data for seven SRPs (sample size ranges from 359,916 to 1,331,010). The fact that whether they share a common genetic etiology remains largely unknown. Late-onset Alzheimer’s disease (AD) is associated with sleep-related phenotypes (SRPs). 5Center for Statistical Science, Peking University, Beijing, China.4Center for Intelligent Public Health, Institute for Artificial Intelligence, Peking University, Beijing, China.3Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, Beijing, China. ![]() 2Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.1Department of Biostatistics, School of Public Health, Peking University, Beijing, China.Dongze Chen 1 Xinpei Wang 1 Tao Huang 2,3,4* Jinzhu Jia 1,5* ![]()
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