Pathway-level transcriptional causal mechanism of sleep disordered breathing

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ABSTRACT Sleep disordered breathing (SDB) affects more than 20% of the older population and increases the risks of multiple cardiometabolic diseases and mortality. Candidate gene and genome-wide association studies (GWASs) have identified genes and pathways associated with SDB. However, the causality is not clear. Transcriptome- wide Mendelian randomization (MR) studies have recently been conducted to elucidate molecular mechanisms of complex diseases. However, the power is limited by the number of tested genes and tissues and small effects of single genes. Building on our preliminary data, we hypothesize that pathway-level transcriptional MR will have better power than single gene MR to identify causal molecular mechanisms for SDB. In this study, we will leverage well-established canonical pathways and existing methods to calculate pathway expression scores, as well as available transcriptomics and genomics data in population-based studies. We will address the following specific aims: 1) To describe tissue-specific and cross-tissue pathway activities using pathway expression scores and identify genetic associations for these scores by performing GWAS; 2) To identify causal associations between pathway activities and SDB by performing MR using GWAS summary statistics of pathway expression scores and SDB traits. Results of this study will advance our knowledge of the molecular basis of SDB, help identify SDB biomarkers, and provide novel treatment targets. This study also will provide a new approach to understand causal mechanisms for other complex diseases.