C100-06 Shared Genetic Architecture Between Sleep Apnea-related Sleep Traits and Cardiometabolic Diseases

Abstract Background Sleep apnea-related sleep traits frequently co-occur with cardiometabolic diseases (CMDs), with shared genetic factors suspected to underlie these associations. However, the contribution of shared genetic determinants to these associations is not fully understood. Methods We conducted a genome-wide pleiotropic association study applying sequential genetic methods to identify shared genetic variants, genes, pathways and causal associations between four sleep apnea-related traits and seven CMDs, including LDSC, high-definition likelihood analysis, colocalization, gene-based tests, enrichment analysis and Mendelian Randomization. Also, validation of those pleiotropic variants was performed in individuals from the All of Us and MVP studies. Findings Among 28 pairs of sleep traits and comorbidities, 23 showed significant genetic correlations. Pleiotropic analysis identified 720 independent SNPs (669 unique) and 92 colocalized loci (85 unique). Among these, 9 SNPs (8 unique) were validated as significantly associated with both traits in the pairs, and notably, rs429358 (19q13.32, APOE) demonstrated pleiotropic effects across sleep apnea, insomnia and type 2 diabetes (T2D). 44 annotated genes were validated by gene-based tests. Shared genes were enriched in phenotypes related to mortality and growth. Pathway analysis highlighted Cushing syndrome, hormone secretion, and cGMP-PKG and calcium signaling pathways. After adjusting for glycemic traits and blood pressure, genetically predicted T2D increased risk of sleep apnea, sleepiness, and snoring. Conversely, sleep apnea was positively associated with heart failure and T2D independently. Interpretation This study of sleep apnea-related sleep traits and CMDs reveals shared genetic determinants that may partially explain the epidemiologic association of these traits and suggests potential novel treatment targets. This abstract is funded by: None